Substituted 6-aza-isoindolin-1-one derivatives

ABSTRACT

Disclosed are compounds of Formula 1, 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, wherein G, p, R 1 , R 2 , R 3a , R 4 , and R 5  are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating disorders, diseases, and conditions involving the immune system and inflammation, including rheumatoid arthritis, cancer, and other disorders, diseases, and conditions for which inhibition of SYK is indicated.

FIELD OF THE INVENTION

This invention relates to substituted 6-aza-isoindolin-1-onederivatives, to pharmaceutical compositions containing them, and totheir use for treating disorders and conditions involving the immunesystem and inflammation, including rheumatoid arthritis. The substituted6-aza-isoindolin-1-one derivatives are inhibitors of spleen tyrosinekinase.

BACKGROUND OF THE INVENTION

Spleen tyrosine kinase (SYK) is a 72 kDa non-receptor cytoplasmictyrosine kinase. SYK has a primary amino acid sequence similar to thatof zeta-associated protein-70 (ZAP-70) and is involved inreceptor-mediated signal transduction. The N-terminal domain of SYKcontains two Src-homology 2 (SH2) domains, which bind todiphosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs)found in the cytoplasmic signaling domains of many immunoreceptorcomplexes. The C-terminus contains the catalytic domain, and includesseveral catalytic loop autophosphorylation sites that are responsiblefor receptor-induced SYK activation and subsequent downstream signalpropagation. SYK is expressed in many cell types involved in adaptiveand innate immunity, including lymphocytes (B cells,Tcells, and NKcells), granulocytes (basophils, neutrophils, and eosinophils),monocytes, macrophages, dendritic cells, and mast cells. SYK isexpressed in other cell types, including airway epithelium andfibroblasts in the upper respiratory system. See, e.g., Martin Turner etal., Immunology Today (2000) 21(3):148-54; and Michael P. Sanderson etal., Inflammation & Allergy—Drug Targets (2009) 8:87-95.

SYK's role in ITAM-dependent signaling and its expression in many celltypes suggest that compounds which inhibit SYK activity may be usefulfor treating disorders involving the immune system and inflammation.Such disorders include Type I hypersensitivity reactions (allergicrhinitis, allergic asthma, and atopic dermatitis); autoimmune diseases(rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus,psoriasis, and immune thrombocytopenic purpura); and inflammation of thelung (chronic obstructive pulmonary disease). See, e.g., Brian R. Wonget al., Expert Opin. Investig. Drugs (2004) 13(7):743-62; Sanderson etal. (2009); Jane Denyer & Vipul Patel, Drug News Perspective (2009)22(3):146-50; Esteban S. Masuda & Jochen Schmitz, Pulmonary Pharmacology& Therapeutics (2008) 21:461-67; Malini Bajpai et al., Expert Opin.Investig. Drugs (2008) 17(5):641-59; and Anna Podolanczuk et al., Blood(2009) 113:3154-60. Other disorders include hematological malignancies,such as acute myeloid leukemia, B-cell chronic lymphocytic leukemia,B-cell lymphoma (e.g., mantle cell lymphoma), and T-cell lymphoma (e.g.,peripheral T-cell lymphoma); as well as epithelial cancers, such as lungcancer, pancreatic cancer, and colon cancer. See, e.g., Cynthia K. Hahnet al., Cancer Cell (2009) 16:281-294; D. H. Chu et al., Immnol. Rev.(1998) 165:167-180; A. L. Feldman et al., Leukemia (2008) 22:1139-43; A.Rinaldi et al., Br. J. Haematol. (2006) 132:303-316; B. Streubel et al.,Leukemia (2006) 20:313-18; Maike Buchner et al., Cancer Research (2009)69(13):5424-32; A. D. Baudot et al., Oncogene (2009) 28:3261-73; andAnurag Singh et al., Cancer Cell (2009) 15:489-500.

Various SYK inhibitors have been described in published patentapplications. See, e.g., EP 1184376 A1; WO 01/83485 A1; WO 03/057695 A1;WO 2006/129100 A1; WO 01/09134 A1; WO 03/063794 A1; WO 2005/012294 A1;WO 2004/087699 A2; WO 2009/026107 A1; WO2009136995 A2; WO2009/145856 A1,and WO 2011/079051 A1.

SUMMARY OF THE INVENTION

This invention provides substituted 6-aza-isoindolin-1-one derivatives,and pharmaceutically acceptable complexes, salts, solvates, and hydratesof the compounds. This invention also provides pharmaceuticalcompositions containing the substituted 6-aza-isoindolin-1-onederivatives, and provides for the use of the compounds to treatdisorders and conditions involving the immune system and inflammation,including rheumatoid arthritis.

One aspect of the invention provides a compound of Formula 1,

or a pharmaceutically acceptable salt thereof, wherein:

-   G is selected from 0 and CH₂;-   R¹ and R² are each independently selected from hydrogen, halo, C₁₋₃    alkyl, and C₁₋₃ haloalkyl; or-   R¹ and R², together with the atom to which they are attached, form a    C₃₋₆ cycloalkylidene;-   each R^(3a) is independently selected from halo, oxo, —NO₂, —CN, R⁶,    and R⁷;-   R⁴ is selected from

-   -   wherein        represents a point of attachment;

-   R^(4a) and R^(4b) are each independently selected from hydrogen,    halo, —CN, R⁶, and R⁷, provided that (a) if R^(4a) is hydrogen, then    R^(4b) is not unsubstituted methyl; (b) if R^(4b) is hydrogen, then    R^(4a) is not hydrogen or unsubstituted methyl; and (c) if R^(4b) is    hydrogen and G is O, then R^(4a) is not chloro; or

-   R^(4a) and R^(4b), together with the atoms to which they are    attached, form a phenylene or a C₃₋₅ heteroarylene, each optionally    substituted with from one to four substituents independently    selected from halo, oxo, —CN, R⁶, and R⁷, wherein the C₃₋₅    heteroarylene moiety has 5 or 6 ring atoms and 1 or 2 are    heteroatoms, each of the heteroatoms being N;

-   R^(4c) is selected from hydrogen, halo, —CN, R⁶, and R⁷, provided    that when G is O, R^(4c) is not unsubstituted methyl;

-   R^(4d) and R^(4e) are each independently selected from hydrogen,    halo, —CN, R⁶, and R⁷; or

-   R^(4d) and R^(4e), together with the atoms to which they are    attached, form a C₃₋₅ heterocycle-diyl or a C₃₋₅ heteroarylene, each    having 5 or 6 ring atoms, at least one heteroatom which is N, and    optionally 1 or 2 additional heteroatoms independently selected from    N, O, and S, and wherein the C₃₋₅ heterocycle-diyl or the C₃₋₅    heteroarylene is optionally substituted with from one to four    substituents independently selected from halo, oxo, —CN, R⁶, and R⁷;

-   R^(4f) is selected from C₃₋₈ cycloalkyl, C₂₋₅ heterocyclyl, C₆₋₁₄    aryl, and C₁₋₉ heteroaryl, each optionally substituted with from one    to five substituents independently selected from halo, oxo, —CN, R⁶,    and R⁷;

-   R^(4g) and R^(4h) are each independently selected from hydrogen,    halo, C₁₋₃ alkyl, and C₁₋₃ haloalkyl; or

-   R^(4g) and R^(4h), together with the atom to which they are    attached, form a C₃₋₆ cycloalkylidene;

-   R⁵ is selected from hydrogen, halo, —CN, C₁₋₄ alkyl, C₂₋₄ alkenyl,    C₂₋₄ alkynyl, C₂₋₅ heterocyclyl, C₁₋₅ heteroaryl, and R¹⁰, wherein    the alkyl, alkenyl, and alkynyl moieties are each optionally    substituted with from one to five substituents independently    selected from halo, —CN, oxo, and R¹⁰, and wherein the heterocyclyl    moiety has 3 to 6 ring atoms and the heteroaryl moiety has 5 or 6    ring atoms, and the heterocyclyl and heteroaryl moieties are each    optionally substituted with from one to four substituents    independently selected from halo, —NO₂, —CN, C₁₋₄ alkyl, C₂₋₄    alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and R¹⁰;

-   each R⁶ is independently selected from —OR⁸, —N(R⁸)R⁹, —NR⁸C(O)R⁹,    —C(O)R⁸, —C(O)OR⁸, —C(O)N(R⁸)R⁹, —C(O)N(R⁸)OR⁹, —C(O)N(R⁸)S(O)₂R⁹,    —N(R⁸)S(O)₂R⁹, —S(O)_(n)R⁸, and —S(O)₂N(R⁸)R⁹;

-   each R⁷ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₃₋₆ cycloalkyl-(CH₂)_(m)—, C₆₋₁₄ aryl-(CH₂)_(m)—,    C₂₋₅ heterocyclyl-(CH₂)_(m)—, and C₁₋₆ heteroaryl-(CH₂)_(m)—, each    optionally substituted with from one to five substituents    independently selected from halo, oxo, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆    haloalkyl, and R¹⁰;

-   each R⁸ and R⁹ is independently selected from hydrogen, C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl-(CH₂)_(m)—, C₆₋₁₄    aryl-(CH₂)_(m)—, C₂₋₅ heterocyclyl-(CH₂)_(m)—, and C₁₋₉    heteroaryl-(CH₂)_(m)—, each non-hydrogen substituent optionally    substituted with from one to five substituents independently    selected from halo, oxo, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and    R¹⁰;

-   each R¹⁰ is independently selected from —OR¹¹, —N(R¹¹)R¹²,    —N(R¹¹)C(O)R¹², —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹¹)R¹²,    —C(O)N(R¹¹)OR¹², —C(O)N(R¹¹)S(O)₂R¹², —NR¹¹S(O)₂R¹², —S(O)—R¹¹, and    —S(O)₂N(R¹¹)R¹²;

-   each R¹¹ and R¹² is independently selected from hydrogen and C₁₋₆    alkyl;

-   each n is independently selected from 0, 1 and 2;

-   each m is independently selected from 0, 1, 2, 3, and 4;

-   each p is independently selected from 0, 1, 2, 3, 4, 5, and 6;

-   wherein each of the heteroaryl moieties recited for R^(4f), R⁷, R⁸,    and R⁹ has 1 to 4 heteroatoms independently selected from N, O, and    S, and each of the heterocyclyl moieties recited for R^(4f), R⁷, R⁸,    and R⁹ has 1 or 2 heteroatoms independently selected from N, O, and    S.

Another aspect of the invention provides a compound which is selectedfrom the following group of compounds and their pharmaceuticallyacceptable salts:

-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-(difluoromethyl)isothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(isothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(isothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-cyclopropylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   5-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiophene-2-carbonitrile;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   5-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiophene-2-carbonitrile;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(5-fluorothiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[2,3-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[2,3-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[3,2-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[3,2-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(6-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(6-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   2-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzo[b]thiophene-5-carbonitrile;-   2-(6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzo[b]thiophene-5-carbonitrile;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(4-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(4-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[3,2-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[3,2-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(4-fluorothiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(4-fluorothiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   Ethyl    2-(6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carboxylate;-   2-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carboxylic    acid;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(1-oxo-2,3-dihydro-1H-pyrrolizin-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(3-methylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(4-fluorostyryl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(4-fluorostyryl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-phenethyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-phenethyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(4-chlorophenethyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((1R,2S)-2-Aminocyclohexylamino)-4-(4-chlorostyryl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(4-chlorostyryl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(indolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   2-(6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carbonitrile;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(7-fluoroindolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-b]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-a]imidazol-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(pyrrolo[2,1-b]oxazol-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(indolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   2-(6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carbonitrile;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(7-fluoroindolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-b]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-a]imidazol-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(pyrrolo[2,1-b]oxazol-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(8-oxo-5,6,7,8-tetrahydroindolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(8-oxo-5,6,7,8-tetrahydroindolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(3-methyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-4-(3,3-dimethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-4-(3-ethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(3-isopropyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(2-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-4-(2-ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(3-methyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-4-(3,3-dimethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-4-(3-ethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(3-isopropyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(2-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-(((1R,2S)-2-Aminocyclohexyl)amino)-4-(2-ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;-   6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;    -   a stereoisomer of any of the aforementioned compounds and their        pharmaceutically acceptable salts.

A further aspect of the invention provides a pharmaceutical compositionwhich includes: a compound of Formula 1, as defined above, or apharmaceutically acceptable salt thereof, or a compound selected fromthe group of compounds defined in the preceding paragraph, or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable excipient.

An additional aspect of the invention provides a use as a medicament ofa compound of Formula 1 or a pharmaceutically acceptable salt thereof,or the use of a compound selected from the group of compounds definedabove or a pharmaceutically acceptable salt thereof.

Another aspect of the invention provides a use of a compound of Formula1 or a pharmaceutically acceptable salt thereof, or the use of acompound selected from the group of compounds defined above or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of a disease or condition for which a SYKinhibitor is indicated.

A further aspect of the invention provides a method of treating adisease or condition in a subject for which a SYK inhibitor isindicated, the method comprising administering to the subject aneffective amount of a compound of Formula 1 or a pharmaceuticallyacceptable salt thereof, or a compound selected from the group ofcompounds defined above or a pharmaceutically acceptable salt thereof.

An additional aspect of the invention provides a method of treating adisease or condition in a subject, the method comprising administeringto the subject an effective amount of a compound of Formula 1 or apharmaceutically acceptable salt thereof, or a compound selected fromthe group of compounds defined above or a pharmaceutically acceptablesalt thereof, wherein the disease or condition is selected from allergicrhinitis, allergic asthma, atopic dermatitis, rheumatoid arthritis,multiple sclerosis, systemic lupus erythematosus, psoriasis, immunethrombocytopenic purpura, inflammatory bowel disease, Behcet's disease,graft versus host disease, chronic obstructive pulmonary disease, andthrombosis.

Another aspect of the invention provides a method of treating a diseaseor condition in a subject, the method comprising administering to thesubject an effective amount of a compound of Formula 1 or apharmaceutically acceptable salt thereof, or a compound selected fromthe group of compounds defined above or a pharmaceutically acceptablesalt thereof, wherein the disease or condition is selected from cancer.

A further aspect of the invention provides a combination of an effectiveamount of a compound of Formula 1 or a pharmaceutically acceptable saltthereof, or a compound selected from the group of compounds definedabove or a pharmaceutically acceptable salt thereof, and at least oneadditional pharmacologically active agent.

DETAILED DESCRIPTION OF THE INVENTION

Unless indicated otherwise, this disclosure uses definitions givenbelow.

“Substituted,” when used in connection with a chemical substituent ormoiety (e.g., an alkyl group), means that one or more hydrogen atoms ofthe substituent or moiety have been replaced with one or morenon-hydrogen atoms or groups, provided that valence requirements are metand that a chemically stable compound results from the substitution.

“About” or “approximately,” when used in connection with a measurablenumerical variable, refers to the indicated value of the variable and toall values of the variable that are within the experimental error of theindicated value or within ±10 percent of the indicated value, whicheveris greater.

“Alkyl” refers to straight chain and branched saturated hydrocarbongroups, generally having a specified number of carbon atoms (e.g., C₁₋₃alkyl refers to an alkyl group having 1 to 3 (i.e., 1, 2 or 3) carbonatoms, C₁₋₆ alkyl refers to an alkyl group having 1 to 6 carbon atoms,and so on). Examples of alkyl groups include methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl,pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl,2,2,2-trimethyleth-1-yl, n-hexyl, and the like.

“Alkenyl” refers to straight chain and branched hydrocarbon groupshaving one or more carbon-carbon double bonds, and generally having aspecified number of carbon atoms. Examples of alkenyl groups includeethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl,1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl,2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl,1,3-butadien-2-yl, and the like.

“Alkynyl” refers to straight chain or branched hydrocarbon groups havingone or more triple carbon-carbon bonds, and generally having a specifiednumber of carbon atoms. Examples of alkynyl groups include ethynyl,1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl,2-butyn-1-yl, and the like.

“Halo,” “halogen” and “halogeno” may be used interchangeably and referto fluoro, chloro, bromo, and iodo.

“Haloalkyl,” “haloalkenyl,” and “haloalkynyl,” refer, respectively, toalkyl, alkenyl, and alkynyl groups substituted with one or more halogenatoms, where alkyl, alkenyl, and alkynyl are defined above, andgenerally having a specified number of carbon atoms. Examples ofhaloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, and the like.

“Cycloalkyl” refers to saturated monocyclic and bicyclic hydrocarbongroups, generally having a specified number of carbon atoms thatcomprise the ring or rings (e.g., C₃₋₈ cycloalkyl refers to a cycloalkylgroup having 3 to 8 carbon atoms as ring members). Bicyclic hydrocarbongroups may include isolated rings (two rings sharing no carbon atoms),spiro rings (two rings sharing one carbon atom), fused rings (two ringssharing two carbon atoms and the bond between the two common carbonatoms), and bridged rings (two rings sharing two carbon atoms, but not acommon bond). The cycloalkyl group may be attached through any ring atomunless such attachment would violate valence requirements. In addition,the cycloalkyl group may include one or more non-hydrogen substituentsunless such substitution would violate valence requirements.

Examples of monocyclic cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of fusedbicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (i.e.,bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, andbicyclo[2.1.0]pentan-5-yl), bicyclo[3.1.0]hexanyl,bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.3.0]octanyl,bicyclo[4.2.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, andthe like. Examples of bridged cycloalkyl groups includebicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl,bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl,bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl,bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, and the like. Examplesof spiro cycloalkyl groups include spiro[3.3]heptanyl,spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl,spiro[3.5]nonanyl, and the like. Examples of isolated bicycliccycloalkyl groups include those derived from bi(cyclobutane),cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane,cyclopentanecyclohexane, bi(cyclohexane), etc.

“Cycloalkylidene” refers to divalent monocyclic cycloalkyl groups, wherecycloalkyl is defined above, which are attached through a single carbonatom of the group, and generally having a specified number of carbonatoms that comprise the ring (e.g., C₃₋₆ cycloalkylidene refers to acycloalkylidene group having 3 to 6 carbon atoms as ring members).Examples include cyclopropylidene, cyclobutylidene, cyclopentylidene,and cyclohexylidene.

“Cycloalkenyl” refers to partially unsaturated monocyclic and bicyclichydrocarbon groups, generally having a specified number of carbon atomsthat comprise the ring or rings. As with cycloalkyl groups, the bicycliccycloalkenyl groups may include isolated, spiro, fused, or bridgedrings. Similarly, the cycloalkenyl group may be attached through anyring atom and may include one or more non-hydrogen substituents unlesssuch attachment or substitution would violate valence requirements.Examples of cycloalkenyl groups include the partially unsaturatedanalogs of the cycloalkyl groups described above, such as cyclobutenyl(i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.

“Aryl” refers to fully unsaturated monocyclic aromatic hydrocarbons andto polycyclic hydrocarbons having at least one aromatic ring, bothmonocyclic and polycyclic aryl groups generally having a specifiednumber of carbon atoms that comprise their ring members (e.g., C₆₋₁₄aryl refers to an aryl group having 6 to 14 carbon atoms as ringmembers). The group may be attached through any ring atom and mayinclude one or more non-hydrogen substituents unless such attachment orsubstitution would violate valence requirements. Examples of aryl groupsinclude phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthalenyl,benzocycloheptanyl, biphenylenyl, fluorenyl, groups derived fromcycloheptatriene cation, and the like.

“Arylene” refers to divalent aryl groups, where aryl is defined above.Examples of arylene groups include phenylene (i.e., benzene-1,2-diyl).

“Heterocycle” and “heterocyclyl” may be used interchangeably and referto saturated or partially unsaturated monocyclic or bicyclic groupshaving ring atoms composed of carbon atoms and 1 to 4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Both themonocyclic and bicyclic groups generally have a specified number ofcarbon atoms in their ring or rings (e.g., C₂₋₅ heterocyclyl refers to aheterocyclyl group having 2 to 5 carbon atoms and 1 to 4 heteroatoms asring members). As with bicyclic cycloalkyl groups, bicyclic heterocyclylgroups may include isolated rings, spiro rings, fused rings, and bridgedrings. The heterocyclyl group may be attached through any ring atom andmay include one or more non-hydrogen substituents unless such attachmentor substitution would violate valence requirements or result in achemically unstable compound. Examples of monocyclic heterocyclyl groupsinclude oxiranyl, thiaranyl, aziridinyl (e.g., aziridin-1-yl andaziridin-2-yl), oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl,tetrahydrothiopheneyl, pyrrolidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl,morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl,thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl,1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl,3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl,1,2,3,4-tetrahydropyridinyl, and 1,2,5,6-tetrahydropyridinyl.

“Heterocycle-diyl” refers to heterocyclyl groups which are attachedthrough two ring atoms of the group, where heterocyclyl is definedabove. They generally have a specified number of carbon atoms in theirring or rings (e.g., C₃₋₅ heterocycle-diyl refers to a heterocycle-diylgroup having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ringmembers). Examples of heterocycle-diyl groups include the multivalentanalogs of the heterocycle groups described above, such asmorpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidinyl-2-ylidene,1-pyridinyl-2-ylidene, 1-(4H)-pyrazolyl-5-ylidene,1-(3H)-imidazolyl-2-ylidene, 3-oxazolyl-2-ylidene,1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, and the like.

“Heteroaromatic” and “heteroaryl” may be used interchangeably and referto unsaturated monocyclic aromatic groups and to polycyclic groupshaving at least one aromatic ring, each of the groups having ring atomscomposed of carbon atoms and 1 to 4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Both the monocyclic and polycyclicgroups generally have a specified number of carbon atoms as ring members(e.g., C₁₋₉ heteroaryl refers to a heteroaryl group having 1 to 9 carbonatoms and 1 to 4 heteroatoms as ring members) and may include anybicyclic group in which any of the above-listed monocyclic heterocyclesare fused to a benzene ring. The heteroaryl group may be attachedthrough any ring atom (or ring atoms for fused rings) and may includeone or more non-hydrogen substituents unless such attachment orsubstitution would violate valence requirements or result in achemically unstable compound. Examples of heteroaryl groups includemonocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, andpyrrol-3-yl), furanyl, thiopheneyl, pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl,1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl,1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl,1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl,pyridazinyl, pyrimidinyl, and pyrazinyl.

Examples of heteroaryl groups also include bicyclic groups such asbenzofuranyl, isobenzofuranyl, benzothiopheneyl, benzo[c]thiopheneyl,indolyl, 3H-indolyl, isoindolyl, 1H-isoindolyl, indolinyl, isoindolinyl,benzimidazolyl, indazolyl, benzotriazolyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl,3H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl,1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl,1H-pyrazolo[3,4-b]pyridinyl, 7H-purinyl, indolizinyl,imidazo[1,2-c]pyridinyl, imidazo[1,5-a]pyridinyl,pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl,imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl,1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl,2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl,pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl,pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl,pyrazino[2,3-b]pyrazinyl, and pyrimido[4,5-d]pyrimidinyl.

“Heteroarylene” refers to heteroaryl groups which are attached throughtwo ring atoms of the group, where heteroaryl is defined above. Theygenerally have a specified number of carbon atoms in their ring or rings(e.g., C₃₋₅ heteroarylene refers to a heteroarylene group having 3 to 5carbon atoms and 1 to 4 heteroatoms as ring members). Examples ofheteroarylene groups include the multivalent analogs of the heteroarylgroups described above, such as pyridine-2,3-diyl, pyridine-3,4-diyl,pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like.

“Oxo” refers to a double bonded oxygen (═O).

“Leaving group” refers to any group that leaves a molecule during afragmentation process, including substitution reactions, eliminationreactions, and addition-elimination reactions. Leaving groups may benucleofugal, in which the group leaves with a pair of electrons thatformerly served as the bond between the leaving group and the molecule,or may be electrofugal, in which the group leaves without the pair ofelectrons. The ability of a nucleofugal leaving group to leave dependson its base strength, with the strongest bases being the poorest leavinggroups. Common nucleofugal leaving groups include nitrogen (e.g., fromdiazonium salts); sulfonates, including alkylsulfonates (e.g.,mesylate), fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate,and tresylate), and arylsulfonates (e.g., tosylate, brosylate,closylate, and nosylate). Others include carbonates, halide ions,carboxylate anions, phenolate ions, and alkoxides. Some stronger bases,such as NH₂ and OH⁻ can be made better leaving groups by treatment withan acid. Common electrofugal leaving groups include the proton, CO₂, andmetals.

“Opposite enantiomer” refers to a molecule that is a non-superimposablemirror image of a reference molecule, which may be obtained by invertingall of the stereogenic centers of the reference molecule. For example,if the reference molecule has S absolute stereochemical configuration,then the opposite enantiomer has R absolute stereochemicalconfiguration. Likewise, if the reference molecule has S,S absolutestereochemical configuration, then the opposite enantiomer has R,Rstereochemical configuration, and so on.

“Stereoisomer” and “stereoisomers” of a compound with givenstereochemical configuration refer to the opposite enantiomer of thecompound and to any diastereoisomers, including geometrical isomers(Z/E) of the compound. For example, if a compound has S,R,Zstereochemical configuration, its stereoisomers would include itsopposite enantiomer having R,S,Z configuration, and its diastereomershaving S,S,Z configuration, R,R,Z configuration, S,R,E configuration,R,S,E configuration, S,S,E configuration, and R,R,E configuration. Ifthe stereochemical configuration of a compound is not specified, then“stereoisomer” refers to any one of the possible stereochemicalconfigurations of the compound.

“Substantially pure stereoisomer” and variants thereof refer to a samplecontaining a compound having a specific stereochemical configuration andwhich comprises at least about 95% of the sample.

“Pure stereoisomer” and variants thereof refer to a sample containing acompound having a specific stereochemical configuration and whichcomprises at least about 99.5% of the sample.

“Subject” refers to a mammal, including a human.

“Pharmaceutically acceptable” substances refers to those substanceswhich are within the scope of sound medical judgment suitable for use incontact with the tissues of subjects without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit-to-risk ratio, and effective for their intended use.

“Treating” refers to reversing, alleviating, inhibiting the progress of,or preventing a disorder, disease or condition to which such termapplies, or to reversing, alleviating, inhibiting the progress of, orpreventing one or more symptoms of such disorder, disease or condition.

“Treatment” refers to the act of “treating,” as defined immediatelyabove.

“Drug,” “drug substance,” “active pharmaceutical ingredient,” and thelike, refer to a compound (e.g., compounds of Formula 1 and compoundsspecifically named above) that may be used for treating a subject inneed of treatment.

“Therapeutically effective amount” of a drug refers to the quantity ofthe drug that may be used for treating a subject and may depend on theweight and age of the subject and the route of administration, amongother things.

“Excipient” refers to any substance that may influence thebioavailability of a drug, but is otherwise pharmacologically inactive.

“Pharmaceutical composition” refers to the combination of one or moredrug substances and one or more excipients.

“Drug product,” “pharmaceutical dosage form,” “dosage form,” “finaldosage form” and the like, refer to a pharmaceutical composition that isadministered to a subject in need of treatment and generally may be inthe form of tablets, capsules, sachets containing powder or granules,liquid solutions or suspensions, patches, films, and the like.

The following abbreviations are used throughout the specification: Ac(acetyl); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); API(active pharmaceutical ingredient); aq (aqueous); Boc(tert-butoxycarbonyl); BSA (bovine serum albumin); Cbz (carbobenzyloxy);dba (dibenzylideneacetone); COD (1,5-cyclooctadiene); DCC(1,3-dicyclohexylcarbodiimide); DCM (dichloromethane); DIPEA(N,N-diisopropylethylamine, Hünig's Base); DMA (N,N-dimethylacetamide);DMAP (4-dimethylaminopyridine); DMARD (disease modifying antirheumaticdrug); DME (1,2-dimethoxyethane); DMF (N,N-dimethylformamide); DMSO(dimethylsulfoxide); dppf (1,1′-bis(diphenylphosphino)ferrocene); DTT(dithiothreitol); EDA ethoxylated dodecyl alcohol, Brj®35); EDCI(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide); EDTA(ethylenediaminetetraacetic acid); ee (enantiomeric excess); eq(equivalents); Et (ethyl); Et₃N (triethyl-amine); EtOAc (ethyl acetate);EtOH (ethanol); FAM (5-carboxyfluorescein); HATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V)); HEPES(4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid); HOAc (aceticacid); HOBt (1H-benzo[d][1,2,3]triazol-1-ol); IC₅₀ (concentration at 50%inhibition); IPA (isopropanol); IPAc (isopropyl acetate); IPE(isopropylether); LDA (lithium diisopropylamide); LiHMDS (lithiumbis(trimethylsilyl)amide); mCPBA (m-chloroperoxybenzoic acid); Me(methyl); MeOH (methanol); MTBE (methyl tert-butyl ether); MOI(multiplicity of infection); mp (melting point); NaOt-Bu (sodiumtertiary butoxide); NBS (N-bromosuccinimide); NCS (N-chlorosuccinimide);NIS (N-iodosuccinimide); PE (petroleum ether); Ph (phenyl); pIC₅₀(−log₁₀(IC₅₀), where IC₅₀ is given in molar (M) units); Pr (propyl);i-Pr (isopropyl); PTFE (polytetrafluoroethylene); RT (room temperature,approximately 20° C. to 25° C.); SYK (spleen tyrosine kinase); TCEP(tris(2-carboxyethyl)phosphine); TFA (trifluoroacetic acid); TFAA(2,2,2-trifluoroacetic anhydride); THF (tetrahydrofuran); Ts (tosyl);and Tris buffer (2-amino-2-hydroxymethyl-propane-1,3-diol buffer).

This disclosure concerns compounds of Formula 1, which includescompounds specifically named above, and their pharmaceuticallyacceptable complexes, salts, solvates and hydrates. This disclosure alsoconcerns materials and methods for preparing compounds of Formula 1,pharmaceutical compositions containing them, and their use for treatingdisorders, diseases, and conditions involving the immune system andinflammation, including rheumatoid arthritis, cancer, includinghematological malignancies, epithelial cancers (i.e., carcinomas), andother disorders, diseases, and conditions for which inhibition of SYK isindicated.

Compounds of Formula 1 also include those in which (a) R¹ is hydrogenand R² is C₁₋₃ alkyl, in particular, methyl or ethyl; (b) R¹ and R² areboth C₁₋₃ alkyl groups, in particular methyl; (c) R¹ and R², togetherwith the carbon atom to which they are attached, form a cyclopropylgroup; or (d) R¹ and R² are both hydrogen atoms.

In addition, or as an alternative to one or more of embodiments (a)through (d) in the preceding paragraph, compounds of Formula 1 includethose in which: (e) R⁵ is hydrogen, halo, or C₁₋₄ alkyl, in particular,methyl or ethyl; (f) R⁵ is hydrogen or halo, or more particularly,chloro or fluoro; or R⁵ is fluoro.

In addition, or as an alternative to one or more of embodiments (a)through (f) in the preceding paragraphs, compounds of Formula 1 includethose in which: (g) p is 0.

In addition, or as an alternative to one or more of embodiments (a)through (g) in the preceding paragraphs, compounds of Formula 1 includethose in which: (h) R⁴ is selected from

(i) R⁴ is

(j) R⁴ is

or (k)

In addition, or as an alternative to one or more of embodiments (a)through (i) in the preceding paragraphs, compounds of Formula 1 includethose in which: (1) R^(4a) is hydrogen, halo, —CN, C₁₋₄ alkyl, inparticular methyl, ethyl, propyl or isopropyl, or is C₃₋₈ cycloalkyl, inparticular cyclopropyl, and R^(4b) is halo, —CN, C₂₋₄ alkyl, inparticular ethyl, propyl or isopropyl, or is C₃₋₈ cycloalkyl, inparticular cyclopropyl; (m) R^(4a) is hydrogen, halo, —CN, methyl,ethyl, propyl, isopropyl or cyclopropyl, and R^(4b) is halo, —CN, ethyl,propyl, isopropyl or cyclopropyl; (n) R^(4a) is fluoro, bromo, —CN, C₂₋₄alkyl, in particular ethyl, propyl or isopropyl, or is C₃₋₈ cycloalkyl,in particular cyclopropyl, and R^(4b) is hydrogen, halo, —CN, C₁₋₄alkyl, in particular methyl, ethyl, propyl or isopropyl, or is C₃₋₈cycloalkyl, in particular cyclopropyl; (o) R^(4a) is fluoro, bromo, —CN,ethyl, propyl, isopropyl or cyclopropyl, and R^(4b) is hydrogen, halo,—CN, methyl, ethyl, propyl, isopropyl or cyclopropyl.

In addition, or as an alternative to one or more of embodiments (a)through (i) in the preceding paragraphs, compounds of Formula 1 includethose in which: (p) R^(4a) and R^(4b), together with the atoms to whichthey are attached, form a phenylene or a C₃₋₅ heteroarylene, eachoptionally substituted with from one to four substituents independentlyselected from halo, oxo, —CN, R⁶, and R⁷, wherein the C₃₋₅ heteroarylenemoiety has 5 or 6 ring atoms and 1 or 2 are heteroatoms, each of theheteroatoms being N.

In addition, or as an alternative to one or more of embodiments (a)through (h) and (j) in the preceding paragraphs, compounds of Formula 1include those in which: (q) R^(4c) is hydrogen, halo, —CN, C₁₋₄ alkyl,in particular methyl, ethyl, propyl, isopropyl, or is C₃₋₈ cycloalkyl,in particular cyclopropyl, provided that when G is O, R^(4c) is notunsubstituted methyl.

In addition, or as an alternative to one or more of embodiments (a)through (h) and (k) in the preceding paragraphs, compounds of Formula 1include those in which: (r) R^(4d) and R^(4e) are each independentlyhydrogen, halo, —CN, C₁₋₄ alkyl, in particular methyl, ethyl, propyl orisopropyl, or C₃₋₈ cycloalkyl, in particular cyclopropyl.

In addition, or as an alternative to one or more of embodiments (a)through (h) and (k) in the preceding paragraphs, compounds of Formula 1include those in which: (s) R^(4d) and R^(4e), together with the atomsto which they are attached, form a C₃₋₅ heterocycle-diyl or a C₃₋₅heteroarylene, each having 5 or 6 ring atoms, at least one heteroatomwhich is N, and optionally 1 or 2 additional heteroatoms independentlyselected from N, O, and S, and wherein the C₃₋₅ heterocycle-diyl or theC₃₋₅ heteroarylene is optionally substituted with from one to foursubstituents independently selected from halo, oxo, —CN, R⁶, and R⁷.

In addition, or as an alternative to one or more of embodiments (a)through (g) in the preceding paragraphs, compounds of Formula 1 includethose in which (t) R⁴ is selected from:

In addition, or as an alternative to one or more of embodiments (a)through (t) in the preceding paragraphs, compounds of Formula 1 includethose in which (u) G is CH₂.

In addition, or as an alternative to one or more of embodiments (a)through (t) in the preceding paragraphs, compounds of Formula 1 includethose in which (v) G is O.

Compounds of Formula 1 also include any of the above embodiments inwhich (w) one or more of the R^(3a), R^(4a), R^(4b), R^(4c), R^(4d),R^(4f), R^(4e), R⁵, R⁷, R₈, and R⁹ substituents have no optionalsubstituents.

Compounds of Formula 1 include (x) those having stereochemicalconfiguration given by Formula 1A:

wherein G, p, R¹, R², R^(3a), R⁴, and R⁵ in Formula 1A are as definedfor Formula 1 or as defined in one or more of embodiments (a) through(w) in the preceding paragraphs.

Compounds of Formula 1 include embodiments (a) through (x) described inthe preceding paragraphs and all compounds specifically named above andin the examples, and generally include all salts, complexes, solvates,hydrates, and liquid crystals of the compounds of Formula 1. Likewise,references to compounds of Formula 1 include all complexes, solvates,hydrates, and liquid crystals of the salts of the compounds of Formula1.

Compounds of Formula 1, which include compounds specifically namedabove, may form pharmaceutically acceptable complexes, salts, solvatesand hydrates. These salts include acid addition salts (includingdi-acids) and base salts. Pharmaceutically acceptable acid additionsalts include nontoxic salts derived from inorganic acids such ashydrochloric acid, nitric acid, phosphoric acid, sulfuric acid,hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorousacids, as well nontoxic salts derived from organic acids, such asaliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoicacids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids,aliphatic and aromatic sulfonic acids, etc. Such salts include acetate,adipate, aspartate, benzoate, besylate, bicarbonate, carbonate,bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate,esylate, formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate,hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate,stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate andxinofoate salts.

Pharmaceutically acceptable base salts include nontoxic salts derivedfrom bases, including metal cations, such as an alkali or alkaline earthmetal cation, as well as amines Examples of suitable metal cationsinclude sodium (Na⁺), potassium (K⁺), magnesium (Mg²⁺), calcium (Ca²⁺),zinc (Zn²⁺), and aluminum (Al³⁺). Examples of suitable amines includearginine, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine,glycine, lysine, N-methylglucamine, olamine,2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussionof useful acid addition and base salts, see S. M. Berge et al., J.Pharm. Sci. (1977) 66:1-19; see also Stahl and Wermuth, Handbook ofPharmaceutical Salts: Properties, Selection, and Use (2002).

Pharmaceutically acceptable salts may be prepared using various methods.For example, one may react a compound of Formula 1 with an appropriateacid or base to give the desired salt. One may also react a precursor ofthe compound of Formula 1 with an acid or base to remove an acid- orbase-labile protecting group or to open a lactone or lactam group of theprecursor. Additionally, one may convert a salt of the compound ofFormula 1 to another salt through treatment with an appropriate acid orbase or through contact with an ion exchange resin. Following reaction,one may then isolate the salt by filtration if it precipitates fromsolution, or by evaporation to recover the salt. The degree ofionization of the salt may vary from completely ionized to almostnon-ionized.

Compounds of Formula 1 may exist in a continuum of solid states rangingfrom fully amorphous to fully crystalline. The term “amorphous” refersto a state in which the material lacks long range order at the molecularlevel and, depending upon temperature, may exhibit the physicalproperties of a solid or a liquid. Typically such materials do not givedistinctive X-ray diffraction patterns and, while exhibiting theproperties of a solid, are more formally described as a liquid. Uponheating, a change from solid to liquid properties occurs which ischaracterized by a change of state, typically second order (“glasstransition”). The term “crystalline” refers to a solid phase in whichthe material has a regular ordered internal structure at the molecularlevel and gives a distinctive X-ray diffraction pattern with definedpeaks. Such materials when heated sufficiently will also exhibit theproperties of a liquid, but the change from solid to liquid ischaracterized by a phase change, typically first order (“meltingpoint”).

Compounds of Formula 1 may also exist in unsolvated and solvated forms.The term “solvate” describes a molecular complex comprising the compoundand one or more pharmaceutically acceptable solvent molecules (e.g.,EtOH). The term “hydrate” is a solvate in which the solvent is water.Pharmaceutically acceptable solvates include those in which the solventmay be isotopically substituted (e.g., D₂O, acetone-d₆, DMSO-d₆).

A currently accepted classification system for solvates and hydrates oforganic compounds is one that distinguishes between isolated site,channel, and metal-ion coordinated solvates and hydrates. See, e.g., K.R. Morris (H. G. Brittain ed.) Polymorphism in Pharmaceutical Solids(1995). Isolated site solvates and hydrates are ones in which thesolvent (e.g., water) molecules are isolated from direct contact witheach other by intervening molecules of the organic compound. In channelsolvates, the solvent molecules lie in lattice channels where they arenext to other solvent molecules. In metal-ion coordinated solvates, thesolvent molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and inhygroscopic compounds, the water or solvent content will depend onhumidity and drying conditions. In such cases, non-stoichiometry willtypically be observed.

Compounds of Formula 1 may also exist as multi-component complexes(other than salts and solvates) in which the compound (drug) and atleast one other component are present in stoichiometric ornon-stoichiometric amounts. Complexes of this type include clathrates(drug-host inclusion complexes) and co-crystals. The latter aretypically defined as crystalline complexes of neutral molecularconstituents which are bound together through non-covalent interactions,but could also be a complex of a neutral molecule with a salt.Co-crystals may be prepared by melt crystallization, byrecrystallization from solvents, or by physically grinding thecomponents together. See, e.g., O. Almarsson and M. J. Zaworotko, Chem.Commun. (2004) 17:1889-1896. For a general review of multi-componentcomplexes, see J. K. Haleblian, J. Pharm. Sci. (1975) 64(8):1269-88.

When subjected to suitable conditions, compounds of Formula 1 may existin a mesomorphic state (mesophase or liquid crystal). The mesomorphicstate lies between the true crystalline state and the true liquid state(either melt or solution). Mesomorphism arising as the result of achange in temperature is described as “thermotropic” and mesomorphismresulting from the addition of a second component, such as water oranother solvent, is described as “lyotropic.” Compounds that have thepotential to form lyotropic mesophases are described as “amphiphilic”and include molecules which possess a polar ionic moiety (e.g.,—COO⁻Na⁺, —COO⁻K⁺, —SO₃ ⁻Na⁺) or polar non-ionic moiety (such as—N⁻N⁺(CH₃)₃). See, e.g., N. H. Hartshorne and A. Stuart, Crystals andthe Polarizing Microscope (4th ed, 1970).

Compounds of Formula 1 generally include all polymorphs and crystalhabits, prodrugs, metabolites, stereoisomers, and tautomers thereof, aswell as all isotopically-labeled compounds thereof.

“Prodrugs” refer to compounds having little or no pharmacologicalactivity that can, when metabolized in vivo, undergo conversion tocompounds having desired pharmacological activity. Prodrugs may beprepared by replacing appropriate functionalities present inpharmacologically active compounds with “pro-moieties” as described, forexample, in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugsinclude ester, ether or amide derivatives of compounds of Formula 1having carboxylic acid, hydroxy, or amino functional groups,respectively. For further discussions of prodrugs, see e.g., T. Higuchiand V. Stella “Pro-drugs as Novel Delivery Systems,” ACS SymposiumSeries 14 (1975) and E. B. Roche ed., Bioreversible Carriers in DrugDesign (1987).

“Metabolites” refer to compounds formed in vivo upon administration ofpharmacologically active compounds. Examples include hydroxymethyl,hydroxy, secondary amino, primary amino, phenol, and carboxylic acidderivatives of compounds of Formula 1 having methyl, alkoxy, tertiaryamino, secondary amino, phenyl, and amide groups, respectively.

Certain compounds described herein may have stereoisomers. Thesecompounds may exist as single enantiomers (enantiopure compounds) ormixtures of enantiomers (enriched and racemic samples), which dependingon the relative excess of one enantiomer over another in a sample, mayexhibit optical activity. Such stereoisomers, which arenon-superimposable mirror images, possess a stereogenic axis or one ormore stereogenic centers (i.e., chirality). Other compounds may bestereoisomers that are not mirror images. Such stereoisomers, which areknown as diastereoisomers, may be chiral or achiral (contain nostereogenic centers). They include molecules containing an alkenyl orcyclic group, so that cis/trans (or Z/E) stereoisomers are possible, ormolecules containing two or more stereogenic centers, in which inversionof a single stereogenic center generates a correspondingdiastereoisomer. Unless stated or otherwise clear (e.g., through use ofstereobonds, stereocenter descriptors, etc.) the scope of the inventionand disclosure generally includes the reference compound and itsstereoisomers, whether they are each pure (e.g., enantiopure) ormixtures (e.g., enantiomerically enriched or racemic).

Geometrical (cis/trans) isomers may be separated by conventionaltechniques such as chromatography and fractional crystallization.

Individual enantiomers of compounds may be prepared via chiral synthesisfrom a suitable optically pure precursor or isolated via resolution ofthe racemate (or the racemate of a salt or derivative) using, forexample, chiral HPLC. Alternatively, the racemate (or a racemicprecursor) may be reacted with a suitable enantiomerically pure compound(e.g., acid or base) to yield a pair of diastereoisomers, each composedof a single enantiomer, which are separated via, say, fractionalrecrystallization or chromatography. The desired enantiomer issubsequently regenerated from the appropriate diastereoisomer. Often,the desired enantiomer may be further enriched by recrystallization in asuitable solvent (e.g., ACN) when it is it available in sufficientquantity (e.g., typically not much less than about 85% ee, and in somecases, not much less than about 90% ee). For a further discussion oftechniques for separating stereoisomers, see E. L. Eliel and S. H.Wilen, Stereochemistry of Organic Compounds (1994).

“Tautomers” refer to structural isomers that are interconvertible via alow energy barrier. Tautomeric isomerism (tautomerism) may take the formof proton tautomerism in which the compound contains, for example, animino, keto, or oxime group, or valence tautomerism in which thecompound contains an aromatic moiety.

Compounds described herein also include all pharmaceutically acceptableisotopic variations, in which at least one atom is replaced by an atomhaving the same atomic number, but an atomic mass different from theatomic mass usually found in nature. Isotopes suitable for inclusion incompounds of Formula 1 include, for example, isotopes of hydrogen, suchas ²H and ³H; isotopes of carbon, such as ¹¹C ¹³C and ¹⁴C; isotopes ofnitrogen, such as ¹³N and ¹⁵N; isotopes of oxygen, such as ¹⁵O, ¹⁷O and¹⁸O; isotopes of sulfur, such as ³⁵S; isotopes of fluorine, such as ¹⁸F;isotopes of chlorine, such as ³⁶Cl, and isotopes of iodine, such as ¹²³Iand ¹²⁵I. Use of isotopic variations (e.g., deuterium, ²H) may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements. Additionally, certain isotopic variations of the disclosedcompounds may incorporate a radioactive isotope (e.g., tritium, ³H, or¹⁴C), which may be useful in drug and/or substrate tissue distributionstudies. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F,¹⁵O and ¹³N may be useful in Positron Emission Topography (PET) studiesfor examining substrate receptor occupancy. Isotopically-labeledcompounds may be prepared by processes analogous to those describedelsewhere in the disclosure using an appropriate isotopically-labeledreagent in place of a non-labeled reagent.

The compounds of Formula 1 may be prepared using the techniquesdescribed below. Some of the schemes and examples may omit details ofcommon reactions, including oxidations, reductions, and so on,separation techniques (extraction, evaporation, precipitation,chromatography, filtration, trituration, crystallization, and the like),and analytical procedures, which are known to persons of ordinary skillin the art of organic chemistry. The details of such reactions andtechniques can be found in a number of treatises, including RichardLarock, Comprehensive Organic Transformations (1999), and themulti-volume series edited by Michael B. Smith and others, Compendium ofOrganic Synthetic Methods (1974 et seq.). Starting materials andreagents may be obtained from commercial sources or may be preparedusing literature methods. Some of the reaction schemes may omit minorproducts resulting from chemical transformations (e.g., an alcohol fromthe hydrolysis of an ester, CO₂ from the decarboxylation of a diacid,etc.). In addition, in some instances, reaction intermediates may beused in subsequent steps without isolation or purification (i.e., insitu).

Starting materials and reagents may be obtained from commercial sourcesor may be prepared using literature methods. For a description of usefulstarting materials and intermediates, see co-pending and commonlyassigned US and PCT published patent applications US 2011-0152273 A1 andWO 2011/079051 A1, both filed 17 Dec. 2010, which are hereinincorporated by reference.

In some of the reaction schemes and examples below, certain compoundscan be prepared using protecting groups, which prevent undesirablechemical reaction at otherwise reactive sites. Protecting groups mayalso be used to enhance solubility or otherwise modify physicalproperties of a compound. For a discussion of protecting groupstrategies, a description of materials and methods for installing andremoving protecting groups, and a compilation of useful protectinggroups for common functional groups, including amines, carboxylic acids,alcohols, ketones, aldehydes, and so on, see T. W. Greene and P. G.Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski,Protective Groups (2000).

Generally, the chemical transformations described throughout thespecification may be carried out using substantially stoichiometricamounts of reactants, though certain reactions may benefit from using anexcess of one or more of the reactants. Additionally, many of thereactions disclosed throughout the specification may be carried out atabout room temperature (RT) and ambient pressure, but depending onreaction kinetics, yields, and so on, some reactions may be run atelevated pressures or employ higher temperatures (e.g., refluxconditions) or lower temperatures (e.g., −78° C. to 0° C.). Anyreference in the disclosure to a stoichiometric range, a temperaturerange, a pH range, etc., whether or not expressly using the word“range,” also includes the indicated endpoints.

Many of the chemical transformations may also employ one or morecompatible solvents, which may influence the reaction rate and yield.Depending on the nature of the reactants, the one or more solvents maybe polar protic solvents (including water), polar aprotic solvents,non-polar solvents, or some combination. Representative solvents includesaturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane,n-octane); aromatic hydrocarbons (e.g., benzene, toluene, xylenes);halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbontetrachloride); aliphatic alcohols (e.g., methanol, ethanol,propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-ol,2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol, hexan-1-ol,2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol,2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol,2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether, di-isopropylether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2-diethoxy-ethane,1-methoxy-2-(2-methoxy-ethoxy)-ethane,1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane);ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate,ethyl acetate); nitrogen-containing solvents (e.g., formamide,N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine,quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbondisulfide, dimethyl sulfoxide, tetrahydro-thiophene-1,1,-dioxide); andphosphorus-containing solvents (e.g., hexamethylphosphoric triamide).

In the schemes, below, substituent identifiers (e.g., R¹, R², R^(3a),R⁴, R⁵, p, G, etc.) are as defined above for Formula 1. As mentionedearlier, however, some of the starting materials and intermediates mayinclude protecting groups, which are removed prior to the final product.In such cases, the substituent identifier refers to moieties defined inFormula 1 and to those moieties with appropriate protecting groups. Forexample, a starting material or intermediate in the schemes may includea substituent identifier (e.g., R⁴) having a potentially reactive amine.In such cases, the substituent identifier would include the protectedmoiety (e.g., with, say, a Boc or Cbz group attached to the amine) aswell as the unprotected moiety.

Scheme 1 shows a method for preparing compound 1-9. Starting material1-0 (2-chloro-3-iodopyridine) undergoes ortho-directed lithiation viatreatment with LDA in THF at −78° C. Quenching with dry ice gives 1-1,which is subsequently esterified at RT using iodomethane and a base(e.g., potassium carbonate). The iodo group of intermediate 1-2 isconverted to a nitrile group via palladium-catalyzed cyanation orthrough treatment with cyanocopper or zinc cyanide in a suitable solvent(e.g., DMF, DMA, etc.) at elevated temperature. The R⁴ substituent isinstalled on 1-3 using a Suzuki reaction, which gives intermediate 1-4.N-oxidation of the pyridine moiety via treatment with hydrogenperoxide/urea complex gives an activated intermediate 1-5, which ischlorinated through reaction with phosphorus oxychloride at an elevatedtemperature (e.g., 90-100° C.). Displacement of the chloro group on 1-6via reaction with an appropriately-substituted amine 1-7 givesintermediate 1-8. Subsequent reduction through palladium-catalyzedhydrogenation and cyclization gives compound 1-9. Here, and in theschemes below, R^(3b) is an amine protecting group. Depending on thenature of the protecting group, hydrogenation may effect removal ofR^(3b) (e.g., when R^(3b) is Cbz, benzyl, etc.) while in others, aseparate deprotection step may be necessary (e.g., treatment with acidwhen R^(3b) is a Boc group).

Scheme 2 depicts the synthesis of compound 2-5. Starting material 2-0(2,6-dichloro-5-fluoronicotinic acid) is lithiated via treatment withLDA in THF at −78° C. Quenching with DMF gives an aldehyde intermediate2-1, which undergoes reductive amination through reaction with an amine(e.g., (2,4-dimethoxyphenyl)methanamine) and reducing agent (e.g.,NaBH(OAc)₃). The resulting amino acid (not shown) is cyclized via amidecoupling, which employs a suitable coupling agent (e.g., EDCI, DCC,etc.), catalyst (HOBt, DMAP, etc.), and solvent (e.g., DMF, DMSO, ACN,THF, DCM, etc.). As in the previous scheme, displacement of the chlorogroup of compound 2-2 with an appropriate amine 1-7 gives intermediate2-3, which is subsequently reacted with a boronic acid or borate (e.g.,R⁴—B(OR¹³)₂, where each R¹³ is H or C₁₋₄ alkyl) in the presence of apalladium catalyst (e.g., Pd(PPh₃)₄, (PPh₃)₂PdCl₂, etc.), base (e.g., KFor Na₂CO₃), and organic solvent (e.g., dioxane, DMF, etc.) at elevatedtemperature (e.g., about 90° C.) to give 2-4. Following the Suzukicoupling, deprotection of the amine and the lactam nitrogen viatreatment of 2-4, e.g. with TFA at elevated temperature (e.g., 40-60°C.) when R^(3b) is a Boc group, generates 2-5.

Scheme 3 depicts an alternate synthesis of compound 2-5. Startingmaterial 3-0 (2,6-dichloro-5-fluoronicotinonitrile) is hydrolyzed bytreatment with concentrated sulfuric acid at elevated temperature (e.g.,about 65° C.) to give amide 3-1, which is lithiated via treatment withLiHMDS at about 0° C. or reaction with LDA in THF at −78° C. Reactionwith DMF gives upon acid workup (e.g., treatment with aqueous HCl) analdehyde (not shown) that cyclizes to form intermediate 3-2. Theintermediate 3-2 is reduced to lactam 3-3 by treatment with a reducingagent (e.g., triethyl silane) and an acid (e.g., TFA) in an organicsolvent (e.g., DCM). Following installation of a Boc protecting group onlactam 3-3, displacement of a chloro group on compound 3-4 via reactionwith an appropriate amine 1-7 gives intermediate 3-5. The intermediateis subsequently reacted with a boronic acid or borate (e.g., R⁴—B(OR¹³)₂in the presence of a palladium catalyst (e.g., Pd(PPh₃)₄, (PPh₃)₂PdCl₂,Pd₂(dba)₃, etc.), an optional ligand (e.g.,2-(dicyclohexylphosphino)biphenyl), a base (e.g., KF or Na₂CO₃), and anorganic solvent (e.g., dioxane, DMF, etc.) to give compound 3-6. TheSuzuki reaction is carried out at elevated temperature (e.g., 90-160°C.), either by conventional heating or via microwave irradiation.Alternatively, compound 3-5 may be reacted with an aromatic tin reagent(e.g., R⁴—Sn(n-Bu)₃) in the presence of a palladium catalyst (e.g.,Pd(PPh₃)₄) and an organic solvent (e.g., toluene) at elevatedtemperature (e.g., about 100° C.). Following the Suzuki or Stillecoupling, deprotection of the amine and the lactam nitrogen viatreatment of 3-6, e.g. with an acid (e.g., TFA or HCl) at RT or above(e.g., 20-60° C.) when R^(3b) is a Boc group, generates 2-5.

Scheme 4 depicts an alternate synthesis of intermediate 3-5. Startingmaterial 3-0 (2,6-dichloro-5-fluoronicotinonitrile) is reacted withpotassium fluoride in anhydrous DMSO to give difluoro intermediate 4-1,which is reacted with a palladium (II) catalyst (e.g., PdCl₂) andacetamide in THF/water at elevated temperature (e.g., about 60° C.). Theresulting amide 4-2 is lithiated via treatment with LiHMDS in THF atabout 0° C. or reaction with LDA in THF at −78° C. Reaction with DMFfollowed by acid workup gives intermediate 4-3, which is reduced tolactam 4-4 by treatment with a reducing agent (e.g., triethyl silane)and an acid (e.g., TFA) in an organic solvent (e.g., DCM). Followinginstallation of a Boc protecting group on lactam 4-4, displacement of afluoro group on compound 4-5 via reaction with an appropriate amine 1-7in the presence of a base (e.g., N-methylmorpholine) and at elevatedtemperature (e.g., about 60° C.) gives intermediate 3-5.

Schemes 5 and 6 show methods for preparing compound 5-7. Startingmaterial 2-1, which may be prepared in accordance with Scheme 2, isreacted with (2,4-dimethoxyphenyl)methanamine in MeOH at roomtemperature. The resulting immine 5-1 is reacted with an organolithiumreagent (R¹—Li) in THF at −78° C. Subsequent treatment with acid giveslactam 5-2, which is reacted with a reducing agent (e.g., triethylsilane) and an acid (e.g., TFA) at reflux conditions to give compound5-3. Following installation of a Boc protecting group on the lactamnitrogen, displacement of a chloro on intermediate 5-4 via reaction withan appropriate amine 1-7 gives intermediate 5-5. The intermediate issubsequently reacted with a boronic acid or borate (e.g., R⁴—B(OR¹³)₂ inthe presence of a palladium catalyst (e.g., Pd(PPh₃)₄, (PPh₃)₂PdCl₂,Pd₂(dba)₃, etc.), an optional ligand (e.g.,2-(dicyclohexylphosphino)biphenyl), a base (e.g., KF or Na₂CO₃), and anorganic solvent (e.g., dioxane, DMF, etc.) to give compound 5-6. TheSuzuki reaction is carried out at elevated temperature (e.g., 90-160°C.), either by conventional heating or via microwave irradiation.Following the Suzuki coupling, deprotection of the amine and lactamnitrogen via treatment of 5-6, e.g. with an acid (e.g., TFA or HCl) atRT or above (e.g., 20-60° C.) when R^(3b) is a Boc group, gives 5-7.

Alternatively, intermediate 5-2 may be reacted with amine 1-7 as shownin Scheme 6 to give intermediate 6-1, which is subsequently reacted witha boronic acid or borate under Suzuki conditions to give compound 6-2.Deprotection yields desired compound 5-7.

Scheme 7 illustrates methods for preparing compounds 7-2, 7-3, 7-4, 7-5,and 7-6. Starting material 7-0, which may be prepared using the methodsdescribed above, may be reacted with NBS or NIS to give halo-pyridineintermediate 7-1 (Y¹ is Br or I). The halo group of 7-1 may be convertedto a nitrile group via palladium-catalyzed cyanation to give 7-2.Compound 7-2 may be subsequently reacted with a Grignard reagent(R⁷—MgBr) to give an imine intermediate (not shown), which upon acidhydrolysis, yields compound 7-3. Alternatively, halo-pyridineintermediate 7-1 may be reacted with NHR⁸R⁹ in the presence of apalladium (II) catalyst (e.g., PdCl₂(dppf)), a stoichiometric amount ofbase (e.g., NaOt—Bu), and an organic solvent (e.g., dioxane, toluene,etc.), at elevated temperature (e.g., about 100° C.). TheBuchwald-Hartwig coupling gives heteroaryl amine 7-4. In addition, 7-1may be reacted with a terminal alkyne (HCR¹³, e.g., R¹³ is H or C₁₋₄alkyl) in the presence of a palladium (II) catalyst (e.g.,(PPh₃)₂PdCl₂), a copper (I) co-catalyst (e.g., CuI), and an amine base(e.g. Et₃N), at RT. Following the Sonogashira coupling, reduction of thealkyne moiety yields compound 7-5 with R⁵ being, e.g., C₁₋₅ alkyl.Compound 7-1 may be reacted with a boronic acid or borate (e.g.,R⁵—B(OR¹³)₂, where R⁵ is C₁₋₉ heteroaryl and e.g., R¹³ is H or C₁₋₄alkyl) in the presence of a palladium catalyst (e.g., Pd(PPh₃)₄,(PPh₃)₂PdCl₂, etc.), a base (e.g., KF or Na₂CO₃), and an organic solvent(e.g., dioxane, DMF, etc.). The Suzuki-type coupling is carried out atelevated temperature (e.g., about 90° C.) and gives compound 7-5 with R⁵being C₁₋₉ heteroaryl.

As shown in Scheme 7, compound 7-0 may alternatively be treated with afluorinating agent, such as SELECTFLUOR®(1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate), in an organic solvent (e.g., DCM) or a mixture oforganic solvents (e.g., DCM and MeOH), to give a fluoro-pyridinederivative 7-6 (Y² is F). Similarly, 7-0 may be treated with achlorinating agent, such as NCS, in an aprotic solvent (e.g., DCM) togive a chloro-pyridine derivative 7-6 (Y² is Cl).

The methods depicted in Schemes 1-7 may be varied as desired. Forexample, protecting groups may be added or removed at various steps inthe routes. In addition, the intermediates may be further elaboratedvia, for example, alkylation, acylation, hydrolysis, oxidation,reduction, amidation, sulfonation, alkynation, alkyenation, and the liketo give the desired final product.

Compounds of Formula 1, which include compounds named above, and theirpharmaceutically acceptable complexes, salts, solvates and hydrates,should be assessed for their biopharmaceutical properties, such assolubility and solution stability across pH, permeability, and the like,to select an appropriate dosage form and route of administration.Compounds that are intended for pharmaceutical use may be administeredas crystalline or amorphous products, and may be obtained, for example,as solid plugs, powders, or films by methods such as precipitation,crystallization, freeze drying, spray drying, evaporative drying,microwave drying, or radio frequency drying.

Compounds of Formula 1 may be administered alone or in combination withone another or with one or more pharmacologically active compounds whichare different than the compounds of Formula 1. Generally, one or morethese compounds are administered as a pharmaceutical composition (aformulation) in association with one or more pharmaceutically acceptableexcipients. The choice of excipients depends on the particular mode ofadministration, the effect of the excipient on solubility and stability,and the nature of the dosage form, among other things. Usefulpharmaceutical compositions and methods for their preparation may befound, for example, in A. R. Gennaro (ed.), Remington: The Science andPractice of Pharmacy (20th ed., 2000).

Compounds of Formula 1 may be administered orally. Oral administrationmay involve swallowing in which case the compound enters the bloodstreamvia the gastrointestinal tract. Alternatively or additionally, oraladministration may involve mucosal administration (e.g., buccal,sublingual, supralingual administration) such that the compound entersthe bloodstream through the oral mucosa.

Formulations suitable for oral administration include solid, semi-solidand liquid systems such as tablets; soft or hard capsules containingmulti- or nano-particulates, liquids, or powders; lozenges which may beliquid-filled; chews; gels; fast dispersing dosage forms; films; ovules;sprays; and buccal or mucoadhesive patches. Liquid formulations includesuspensions, solutions, syrups and elixirs. Such formulations may beemployed as fillers in soft or hard capsules (made, e.g., from gelatinor hydroxypropylmethylcellulose) and typically comprise a carrier (e.g.,water, ethanol, polyethylene glycol, propylene glycol, methylcellulose,or a suitable oil) and one or more emulsifying agents, suspending agentsor both. Liquid formulations may also be prepared by the reconstitutionof a solid (e.g., from a sachet).

Compounds of Formula 1 may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in Liang andChen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986.

For tablet dosage forms, depending on dose, the active pharmaceuticalingredient (API) may comprise from about 1 wt % to about 80 wt % of thedosage form or more typically from about 5 wt % to about 60 wt % of thedosage form. In addition to the API, tablets may include one or moredisintegrants, binders, diluents, surfactants, glidants, lubricants,anti-oxidants, colorants, flavoring agents, preservatives, andtaste-masking agents. Examples of disintegrants include sodium starchglycolate, sodium carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone,methyl cellulose, microcrystalline cellulose, C₁₋₆ alkyl-substitutedhydroxypropylcellulose, starch, pregelatinized starch, and sodiumalginate. Generally, the disintegrant will comprise from about 1 wt % toabout 25 wt % or from about 5 wt % to about 20 wt % of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose andhydroxypropylmethylcellulose. Tablets may also contain diluents, such aslactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol,xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starchand dibasic calcium phosphate dihydrate.

Tablets may also include surface active agents, such as sodium laurylsulfate and polysorbate 80, and glidants such as silicon dioxide andtalc. When present, surface active agents may comprise from about 0.2 wt% to about 5 wt % of the tablet, and glidants may comprise from about0.2 wt % to about 1 wt % of the tablet.

Tablets may also contain lubricants such as magnesium stearate, calciumstearate, zinc stearate, sodium stearyl fumarate, and mixtures ofmagnesium stearate with sodium lauryl sulfate. Lubricants may comprisefrom about 0.25 wt % to about 10 wt % or from about 0.5 wt % to about 3wt % of the tablet.

Tablet blends may be compressed directly or by roller compaction to formtablets. Tablet blends or portions of blends may alternatively be wet-,dry-, or melt-granulated, melt congealed, or extruded before tableting.If desired, prior to blending one or more of the components may be sizedby screening or milling or both. The final dosage form may comprise oneor more layers and may be coated, uncoated, or encapsulated. Exemplarytablets may contain up to about 80 wt % of API, from about 10 wt % toabout 90 wt % of binder, from about 0 wt % to about 85 wt % of diluent,from about 2 wt % to about 10 wt % of disintegrant, and from about 0.25wt % to about 10 wt % of lubricant. For a discussion of blending,granulation, milling, screening, tableting, coating, as well as adescription of alternative techniques for preparing drug products, seeA. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy(20th ed., 2000); H. A. Lieberman et al. (ed.), Pharmaceutical DosageForms: Tablets, Vol. 1-3 (2d ed., 1990); and D. K. Parikh & C. K.Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81(1997).

Consumable oral films for human or veterinary use are pliablewater-soluble or water-swellable thin film dosage forms which may berapidly dissolving or mucoadhesive. In addition to the API, a typicalfilm includes one or more film-forming polymers, binders, solvents,humectants, plasticizers, stabilizers or emulsifiers,viscosity-modifying agents, and solvents. Other film ingredients mayinclude anti-oxidants, colorants, flavorants and flavor enhancers,preservatives, salivary stimulating agents, cooling agents, co-solvents(including oils), emollients, bulking agents, anti-foaming agents,surfactants, and taste-masking agents. Some components of theformulation may perform more than one function.

In addition to dosing requirements, the amount of API in the film maydepend on its solubility. If water soluble, the API would typicallycomprise from about 1 wt % to about 80 wt % of the non-solventcomponents (solutes) in the film or from about 20 wt % to about 50 wt %of the solutes in the film. A less soluble API may comprise a greaterproportion of the composition, typically up to about 88 wt % of thenon-solvent components in the film.

The film-forming polymer may be selected from natural polysaccharides,proteins, or synthetic hydrocolloids and typically comprises from about0.01 wt % to about 99 wt % or from about 30 wt % to about 80 wt % of thefilm.

Film dosage forms are typically prepared by evaporative drying of thinaqueous films coated onto a peelable backing support or paper, which maycarried out in a drying oven or tunnel (e.g., in a combinedcoating-drying apparatus), in lyophilization equipment, or in a vacuumoven.

Useful solid formulations for oral administration may include immediaterelease formulations and modified release formulations. Modified releaseformulations include delayed-, sustained-, pulsed-, controlled-,targeted-, and programmed-release. For a general description of suitablemodified release formulations, see U.S. Pat. No. 6,106,864. For detailsof other useful release technologies, such as high energy dispersionsand osmotic and coated particles, see Verma et al, PharmaceuticalTechnology On-line (2001) 25(2):1-14.

Compounds of Formula 1 may also be administered directly into the bloodstream, muscle, or an internal organ of the subject. Suitable techniquesfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular, intrasynovial, andsubcutaneous administration. Suitable devices for parenteraladministration include needle injectors, including microneedleinjectors, needle-free injectors, and infusion devices.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(e.g., pH of from about 3 to about 9). For some applications, however,compounds of Formula 1 may be more suitably formulated as a sterilenon-aqueous solution or as a dried form to be used in conjunction with asuitable vehicle such as sterile, pyrogen-free water. The preparation ofparenteral formulations under sterile conditions (e.g., bylyophilization) may be readily accomplished using standardpharmaceutical techniques.

The solubility of compounds which are used in the preparation ofparenteral solutions may be increased through appropriate formulationtechniques, such as the incorporation of solubility-enhancing agents.Formulations for parenteral administration may be formulated to beimmediate or modified release. Modified release formulations includedelayed, sustained, pulsed, controlled, targeted, and programmedrelease. Thus, compounds of Formula 1 may be formulated as a suspension,a solid, a semi-solid, or a thixotropic liquid for administration as animplanted depot providing modified release of the active compound.Examples of such formulations include drug-coated stents and semi-solidsand suspensions comprising drug-loaded poly(DL-lactic-coglycolic)acid(PGLA) microspheres.

Compounds of Formula 1 may also be administered topically,intradermally, or transdermally to the skin or mucosa. Typicalformulations for this purpose include gels, hydrogels, lotions,solutions, creams, ointments, dusting powders, dressings, foams, films,skin patches, wafers, implants, sponges, fibers, bandages andmicroemulsions. Liposomes may also be used. Typical carriers may includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Topical formulationsmay also include penetration enhancers. See, e.g., Finnin and Morgan, J.Pharm. Sci. 88(10):955-958 (1999).

Other means of topical administration include delivery byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g. Powderject™ and Bioject™) injection.Formulations for topical administration may be formulated to beimmediate or modified release as described above.

Compounds of Formula 1 may also be administered intranasally or byinhalation, typically in the form of a dry powder, an aerosol spray, ornasal drops. An inhaler may be used to administer the dry powder, whichcomprises the API alone, a powder blend of the API and a diluent, suchas lactose, or a mixed component particle that includes the API and aphospholipid, such as phosphatidylcholine. For intranasal use, thepowder may include a bioadhesive agent, e.g., chitosan or cyclodextrin.A pressurized container, pump, sprayer, atomizer, or nebulizer, may beused to generate the aerosol spray from a solution or suspensioncomprising the API, one or more agents for dispersing, solubilizing, orextending the release of the API (e.g., EtOH with or without water), oneor more solvents (e.g., 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane) which serve as a propellant, and anoptional surfactant, such as sorbitan trioleate, oleic acid, or anoligolactic acid. An atomizer using electrohydrodynamics may be used toproduce a fine mist.

Prior to use in a dry powder or suspension formulation, the drug productis usually comminuted to a particle size suitable for delivery byinhalation (typically 90% of the particles, based on volume, having alargest dimension less than 5 microns). This may be achieved by anyappropriate size reduction method, such as spiral jet milling, fluid bedjet milling, supercritical fluid processing, high pressurehomogenization, or spray drying.

Capsules, blisters and cartridges (made, for example, from gelatin orhydroxypropylmethyl cellulose) for use in an inhaler or insufflator maybe formulated to contain a powder mixture of the active compound, asuitable powder base such as lactose or starch, and a performancemodifier such as L-leucine, mannitol, or magnesium stearate. The lactosemay be anhydrous or monohydrated. Other suitable excipients includedextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, andtrehalose.

A suitable solution formulation for use in an atomizer usingelectrohydrodynamics to produce a fine mist may contain from about 1 μgto about 20 mg of the API per actuation and the actuation volume mayvary from about 1 μL to about 100 μL. A typical formulation may compriseone or more compounds of Formula 1, propylene glycol, sterile water,EtOH, and NaCl. Alternative solvents, which may be used instead ofpropylene glycol, include glycerol and polyethylene glycol.

Formulations for inhaled administration, intranasal administration, orboth, may be formulated to be immediate or modified release using, forexample, PGLA. Suitable flavors, such as menthol and levomenthol, orsweeteners, such as saccharin or sodium saccharin, may be added toformulations intended for inhaled/intranasal administration.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve that delivers a metered amount. Units aretypically arranged to administer a metered dose or “puff” containingfrom about 10 μg to about 1000 μg of the API. The overall daily dosewill typically range from about 100 μg to about 10 mg which may beadministered in a single dose or, more usually, as divided dosesthroughout the day.

The active compounds may be administered rectally or vaginally, e.g., inthe form of a suppository, pessary, or enema. Cocoa butter is atraditional suppository base, but various alternatives may be used asappropriate. Formulations for rectal or vaginal administration may beformulated to be immediate or modified release as described above.

Compounds of Formula 1 may also be administered directly to the eye orear, typically in the form of drops of a micronized suspension orsolution in isotonic, pH-adjusted, sterile saline. Other formulationssuitable for ocular and aural administration include ointments, gels,biodegradable implants (e.g. absorbable gel sponges, collagen),non-biodegradable implants (e.g. silicone), wafers, lenses, andparticulate or vesicular systems, such as niosomes or liposomes. Theformulation may include one or more polymers and a preservative, such asbenzalkonium chloride. Typical polymers include crossed-linkedpolyacrylic acid, polyvinylalcohol, hyaluronic acid, cellulosic polymers(e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose), and heteropolysaccharide polymers (e.g., gelan gum). Suchformulations may also be delivered by iontophoresis. Formulations forocular or aural administration may be formulated to be immediate ormodified release as described above.

To improve their solubility, dissolution rate, taste-masking,bioavailability, or stability, compounds of Formula 1 may be combinedwith soluble macromolecular entities, including cyclodextrin and itsderivatives and polyethylene glycol-containing polymers. For example,API-cyclodextrin complexes are generally useful for most dosage formsand routes of administration. Both inclusion and non-inclusion complexesmay be used. As an alternative to direct complexation with the API, thecyclodextrin may be used as an auxiliary additive, i.e. as a carrier,diluent, or solubilizer. Alpha-, beta- and gamma-cyclodextrins arecommonly used for these purposes. See, e.g., WO 91/11172, WO 94/02518,and WO 98/55148.

As noted above, one or more compounds of Formula 1, including compoundsspecifically named above, and their pharmaceutically active complexes,salts, solvates and hydrates, may be combined with each other or withone or more other active pharmaceutically active compounds to treatvarious diseases, conditions and disorders. In such cases, the activecompounds may be combined in a single dosage form as described above ormay be provided in the form of a kit which is suitable forcoadministration of the compositions. The kit comprises (1) two or moredifferent pharmaceutical compositions, at least one of which contains acompound of Formula 1; and (2) a device for separately retaining the twopharmaceutical compositions, such as a divided bottle or a divided foilpacket. An example of such a kit is the familiar blister pack used forthe packaging of tablets or capsules. The kit is suitable foradministering different types of dosage forms (e.g., oral andparenteral) or for administering different pharmaceutical compositionsat separate dosing intervals, or for titrating the differentpharmaceutical compositions against one another. To assist with patientcompliance, the kit typically comprises directions for administrationand may be provided with a memory aid.

For administration to human patients, the total daily dose of theclaimed and disclosed compounds is typically in the range of about 0.1mg to about 3000 mg depending on the route of administration. Forexample, oral administration may require a total daily dose of fromabout 1 mg to about 3000 mg, while an intravenous dose may only requirea total daily dose of from about 0.1 mg to about 300 mg. The total dailydose may be administered in single or divided doses and, at thephysician's discretion, may fall outside of the typical ranges givenabove. Although these dosages are based on an average human subjecthaving a mass of about 60 kg to about 70 kg, the physician will be ableto determine the appropriate dose for a patient (e.g., an infant) whosemass falls outside of this weight range.

As noted above, the compounds of Formula 1 may be used to treatdisorders, diseases, and conditions for which inhibition of SYK isindicated. Such disorders, diseases, and conditions generally relate toany unhealthy or abnormal state in a subject for which the inhibition ofSYK provides a therapeutic benefit. More particularly, such disorders,diseases, and conditions may involve the immune system and inflammation,including Type I hypersensitivity (allergic) reactions (allergicrhinitis, allergic asthma, and atopic dermatitis); autoimmune diseases(rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus,psoriasis, and immune thrombocytopenic purpura); inflammation of thelung (chronic obstructive pulmonary disease) and thrombosis. Thecompounds of Formula 1 may also be used to treat disorders, diseases,and conditions related to abnormal cell growth, including hematologicalmalignancies, such as acute myeloid leukemia, B-cell chronic lymphocyticleukemia, B-cell lymphoma (e.g., mantle cell lymphoma), and T-celllymphoma (e.g., peripheral T-cell lymphoma), as well as epithelialcancers (i.e., carcinomas), such as lung cancer (small cell lung cancerand non-small cell lung cancer), pancreatic cancer, and colon cancer.

In addition to the hematological malignancies and epithelial cancersnoted above, the compounds of Formula 1 may also be used to treat othertypes of cancer, including leukemia (chronic myelogenous leukemia andchronic lymphocytic leukemia); breast cancer, genitourinary cancer, skincancer, bone cancer, prostate cancer, and liver cancer; brain cancer;cancer of the larynx, gall bladder, rectum, parathyroid, thyroid,adrenal, neural tissue, bladder, head, neck, stomach, bronchi, andkidneys; basal cell carcinoma, squamous cell carcinoma, metastatic skincarcinoma, osteosarcoma, Ewing's sarcoma, veticulum cell sarcoma, andKaposi's sarcoma; myeloma, giant cell tumor, islet cell tumor, acute andchronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma,medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinalganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitustumor, Wilms' tumor, seminoma, ovarian tumor, leiomyomater tumor,cervical dysplasia, neuroblastoma, retinoblastoma, myelodysplasticsyndrome, rhabdomyosarcoma, astrocytoma, non-Hodgkin's lymphoma,malignant hypercalcemia, polycythermia vera, adenocarcinoma,glioblastoma multiforma, glioma, lymphomas, and malignant melanomas,among others.

In addition to cancer, the compounds of Formula 1 may also be used totreat other diseases related to abnormal cell growth, includingnon-malignant proliferative diseases such as benign prostatichypertrophy, restinosis, hyperplasia, synovial proliferation disorder,retinopathy or other neovascular disorders of the eye, among others.

The compounds of Formula 1 may also be used to treat autoimmunedisorders in addition to those listed above. Such disorders, diseases,and conditions include Crohns disease, dermatomyositis, diabetesmellitus type 1, Goodpasture's syndrome, Graves' disease, Guillain-Barrésyndrome, Hashimoto's disease, mixed connective tissue damage,myasthenia gravis, narcolepsy, pemphigus vulgaris, pernicious anemia,polymyositis, primary biliary cirrhosis, Sjögren's syndrome, temporalarteritis, ulcerative colitis, vasculitis, and Wegener's granulomatosis,among others.

Furthermore, compounds of Formula 1 may be used to treat inflammatorydisorders including asthma, chronic inflammation, chronic prostatitis,glomerulonephritis, hypersensitivities, inflammatory bowel diseases(ulcerative colitis in addition to Crohn's disease), pelvic inflammatorydisease, reperfusion injury, transplant rejection, graft versus hostdisease, vasculitis, and systemic inflammatory response syndrome.

The compounds of Formula 1 may also be used to treat specific diseasesthat may fall within one or more general disorders described above,including arthritis. In addition to rheumatoid arthritis, Sjögren'ssyndrome, systemic lupus erythematosus, SLE in children and adolescents,compounds of Formula 1 may also be used to treat other arthritisdiseases, including ankylosing spondylitis, avascular necrosis, Behcet'sdisease, bursitis, calcium pyrophosphate dihyrate crystal depositiondisease (pseudo gout), carpal tunnel syndrome, Ehlers-Danlos syndrome,fibromyalgia, Fifth disease, giant cell arteritis, gout, juveniledermatomyositis, juvenile rheumatoid arthritis, juvenilespondyloarthopathy, Lyme disease, Marfan syndrome, myositis,osteoarthritis, osteogenesis imperfect, osteoporosis, Paget's disease,psoriatic arthritis, Raynaud's phenomenon, reactive arthritis, reflexsympathetic dystrophy syndrome, scleroderma, spinal stenosis, Still'sdisease, and tendinitis, among others.

The claimed and disclosed compounds may be combined with one or moreother pharmacologically active compounds or therapies for the treatmentof one or more disorders, diseases or conditions for which SYK isindicated, including disorders, diseases, and conditions involving theimmune system, inflammation, and abnormal cell growth. For example,compounds of Formula 1, which include compounds specifically namedabove, and their pharmaceutically acceptable complexes, salts, solvatesand hydrates, may be administered simultaneously, sequentially orseparately in combination with one or more compounds or therapies fortreating arthritis, including rheumatoid arthritis and osteoarthritis,or for treating cancer, including hematological malignancies, such asacute myeloid leukemia, B-cell chronic lymphocytic leukemia, B-celllymphoma, and T-cell lymphoma, and carcinomas, such as lung cancer,pancreatic cancer, and colon cancer. Such combinations may offersignificant therapeutic advantages, including fewer side effects,improved ability to treat underserved patient populations, orsynergistic activity.

For example, when used to treat arthritis, the compounds of Formula 1may be combined with one or more nonsteroidal anti-inflammatory drugs(NSAIDs), analgesics, corticosteroids, biological response modifiers,and protein-A immunoadsorption therapy. Alternatively or additionally,when treating rheumatoid arthritis, the compounds of Formula 1 may becombined with one or more disease modifying antirheumatic drugs(DMARDs), and when treating osteoarthritis, the compounds of Formula 1may be combined with one or more osteoporosis agents.

Representative NSAIDs include apazone, aspirin, celecoxib, diclofenac(with and without misoprostol), diflunisal, etodolac, fenoprofen,flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium,mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin,phenylbutazone, piroxicam, choline and magnesium salicylates, salsalate,and sulindac. Representative analgesics include acetaminophen andmorphine sulfate, as well as codeine, hydrocodone, oxycodone,propoxyphene, and tramadol, all with or without acetaminophen.Representative corticosteroids include betamethasone, cortisone acetate,dexamethasone, hydrocortisone, methylprednisolone, prednisolone, andprednisone. Representative biological response modifiers include TNF-αinhibitors, such as adalimumab, etanercept, and infliximab; selectiveB-cell inhibitors, such as rituximab; IL-1 inhibitors, such as anakinra,and selective costimulation modulators, such as abatacept.

Representative DMARDs include auranofin (oral gold), azathioprine,chlorambucil, cyclophosamide, cyclosporine, gold sodium thiomalate(injectable gold), hydroxychloroquine, leflunomide, methotrexate,minocycline, myophenolate mofetil, penicillamine, and sulfasalazine.Representative osteoporosis agents include bisphosphonates, such asalendronate, ibandronate, risedronate, and zoledronic acid; selectiveestrogen receptor modulators, such as droloxifene, lasofoxifene, andraloxifene; hormones, such as calcitonin, estrogens, and parathyroidhormone; and immunosuppressant agents such as azathioprine,cyclosporine, and rapamycin.

Particularly useful combinations for treating rheumatoid arthritisinclude a compound of Formula 1 and methotrexate; a compound of Formula1 and one or more biological response modifiers, such as lefluonomide,etanercept, adalimumab, and infliximab; or a compound of Formula 1,methotrexate, and one or more biological response modifiers, such aslefluonomide, etanercept, adalimumab, and infliximab.

For the treatment of thrombis and restensosis, the compounds of Formula1 may be combined with one or more cardiovascular agents such as calciumchannel blockers, statins, fibrates, beta-blockers, ACE inhibitors, andplatelet aggregation inhibitors.

The compounds of Formula 1 may also be combined with one or morecompounds or therapies for treating cancer. These includechemotherapeutic agents (i.e., cytotoxic or antineoplastic agents) suchas alkylating agents, antibiotics, antimetabolic agents, plant-derivedagents, and topoisomerase inhibitors, as well as molecularly targeteddrugs which block the growth and spread of cancer by interfering withspecific molecules involved in tumor growth and progression. Molecularlytargeted drugs include both small molecules and biologics.

Representative alkylating agents include bischloroethylamines (nitrogenmustards, e.g., chlorambucil, cyclophosphamide, ifosfamide,mechlorethamine, melphalan, and uracil mustard); aziridines (e.g.,thiotepa); alkyl alkone sulfonates (e.g., busulfan); nitrosoureas (e.g.,carmustine, lomustine, and streptozocin); nonclassical alkylating agents(e.g., altretamine, dacarbazine, and procarbazine); and platinumcompounds (e.g., carboplatin, cisplatin, nedaplatin, oxaliplatin,satraplatin, and triplatin tetranitrate).

Representative antibiotic agents include anthracyclines (e.g.,aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin,idarubicin, pirarubicin, valrubicin, and zorubicin); anthracenediones(e.g., mitoxantrone and pixantrone); and streptomyces (e.g.,actinomycin, bleomycin, dactinomycin, mitomycin C, and plicamycin).

Representative antimetabolic agents include dihydrofolate reductaseinhibitors (e.g., aminopterin, methotrexate, and pemetrexed); hymidylatesynthase inhibitors (e.g., raltitrexed and pemetrexed); folinic acid(e.g., leucovorin); adenosine deaminase inhibitors (e.g., pentostatin);halogenated/ribonucleotide reductase inhibitors (e.g., cladribine,clofarabine, and fludarabine); thiopurines (e.g., thioguanine andmercaptopurine); thymidylate synthase inhibitors (e.g., fluorouracil,capecitabine, tegafur, carmofur, and floxuridine); DNA polymeraseinhibitors (e.g., cytarabine); ribonucleotide reductase inhibitors(e.g., gemcitabine); hypomethylating agent (e.g., azacitidine anddecitabine); and ribonucleotide reductase inhibitor (e.g., hydroxyurea);and an asparagine depleter (e.g., asparaginase)

Representative plant-derived agents include vinca alkaloids (e.g.,vincristine, vinblastine, vindesine, vinzolidine, and vinorelbine),podophyllotoxins (e.g., etoposide and teniposide), and taxanes (e.g.,docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel).

Representative type I topoisomerase inhibitors include camptothecins,such as belotecan, irinotecan, rubitecan, and topotecan. Representativetype II topoisomerase inhibitors include amsacrine, etoposide, etoposidephosphate, and teniposide, which are derivatives of epipodophyllotoxins.

Molecularly targeted therapies include biologic agents such as cytokinesand other immune-regulating agents. Useful cytokines includeinterleukin-2 (IL-2, aldesleukin), interleukin 4 (IL-4), interleukin 12(IL-12), and interferon, which includes more than 23 related subtypes.Other cytokines include granulocyte colony stimulating factor (CSF)(filgrastim) and granulocyte macrophage CSF (sargramostim). Otherimmuno-modulating agents include bacillus Calmette-Guerin, levamisole,and octreotide; monoclonal antibodies against tumor antigens, such astrastruzumab and rituximab; and cancer vaccines, which induce an immuneresponse to tumors.

In addition, molecularly targeted drugs that interfere with specificmolecules involved in tumor growth and progression include inhibitors ofepidermal growth factor (EGF), transforming growth factor-alpha(TGF_(α)), TGF_(β), heregulin, insulin-like growth factor (IGF),fibroblast growth factor (FGF), keratinocyte growth factor (KGF), colonystimulating factor (CSF), erythropoietin (EPO), interleukin-2 (IL-2),nerve growth factor (NGF), platelet-derived growth factor (PDGF),hetaptocyte growth factor (HGF), vascular endothelial growth factor(VEGF), angiopoietin, epidermal growth factor receptor (EGFR), humanepidermal growth factor receptor 2 (HER2), HER4, insulin-like growthfactor 1 receptor (IGF1R), IGF2R, fibroblast growth factor 1 receptor(FGF1R), FGF2R, FGF3R, FGF4R, vascular endothelial growth factorreceptor (VEGFR), tyrosine kinase with immunoglobulin-like and epidermalgrowth factor-like domains 2 (Tie-2), platelet-derived growth factorreceptor (PDGFR), Abl, Bcr-Abl, Raf, FMS-like tyrosine kinase 3 (FLT3),c-Kit, Src, protein kinase c (PKC), tropomyosin receptor kinase (Trk),Ret, mammalian target of rapamycin (mTOR), Aurora kinase, polo-likekinase (PLK), mitogen activated protein kinase (MAPK),mesenchymal-epithelial transition factor (c-MET), cyclin-dependantkinase (CDK), Akt, extracellular signal-regulated kinases (ERK),poly(ADP) ribose polymerase (PARP), and the like.

Specific molecularly targeted drugs include selective estrogen receptormodulators, such as tamoxifen, toremifene, fulvestrant, and raloxifene;antiandrogens, such as bicalutamide, nilutamide, megestrol, andflutamide; and aromatase inhibitors, such as exemestane, anastrozole,and letrozole. Other specific molecularly targeted drugs include agentswhich inhibit signal transduction, such as imatinib, dasatinib,nilotinib, trastuzumab, gefitinib, erlotinib, cetuximab, lapatinib,panitumumab, and temsirolimus; agents that induce apoptosis, such asbortezomib; agents that block angiogensis, such as bevacizumab,sorafenib, and sunitinib; agents that help the immune system destroycancel cells, such as rituximab and alemtuzumab; and monoclonalantibodies which deliver toxic molecules to cancer cells, such asgemtuzumab ozogamicin, tositumomab, 131I-tositumoab, and ibritumomabtiuxetan.

Biological Activity: SYK Inhibition

The ability of compounds to inhibit SYK activity may be assessed using avariety of methods, including in vitro and in vivo assays. The followingin vitro assay measures a test compound's ability to inhibitSYK-mediated phosphorylation of a FAM-labeled SYK-specific substrate(5FAM-KKKKEEIYFFFG-NH₂).

SYK protein is prepared from cDNA encoding human spleen tyrosine kinaseand is expressed in insect cells using a baculovirus expression vector.The cDNA (IMAGE: 3542895) is purchased from Open Biosystems. The SYKkinase domain (residues 356-635) is amplified via PCR and cloned intoplasmid pFastBacl (Invitrogen) at BamHI/XbaI sites. Recombinant plasmidencoding Met-Ala-Lys-SYK(356-635)-HHHHHH is sequenced and transformedinto E. coli DH10Bac strain. The recombinant bacmid DNA is isolated andtransfected into Sf9 insect cells. Recombinant virus is harvested 72 hafter transfection. High titer viral stock is prepared by infecting Sf9cells at a multiplicity of infection (MOI) of approximately 0.01. Asuspension of Sf9 cells (10 L) is infected with recombinant virus(MOI=5) and is incubated in a Wave Bioreactor (GE-Healthcare) for 48 h.The cells are harvested and stored at −80° C.

To purify the expressed protein, the frozen Sf9 cells (10 L) are brokeninto small (<1 cm) particles and suspended in a lysis buffer (300 mL)containing 20 mM Tris (pH 7.6), 0.25 mM TCEP, 100 mM NaCl, 5% glyceroland a protease inhibitor. The suspension is stirred at RT untilcompletely thawed, lysed an additional 2-4 min on a rotary bladehomogenizer, and then centrifuged at 4200 g for 1 h. Followingcentrifugation, the supernatant is poured through cheese cloth andcombined with a nickel chelating resin (Probond Resin™, Invitrogen)which is pre-equilibrated in a wash buffer containing 10 mM Tris (pH7.6), 0.25 mM TCEP, 300 mM NaCl, 5% glycerol, and 20 mM imidazole. Themixture is agitated for 3 h in a cold room and then centrifuged at 900 gfor 10 min. The resin is dispersed in wash buffer (50 mL), centrifugedfor 10 min at 900 g, re-dispersed in a small amount of wash buffer (5mL), and then pour into a disposable Poly-Prep chromatography column,through which wash buffer is passed by gravity until no protein isobserved in coomassie buffer (about 120 mL of wash buffer). An elutionbuffer (30 mL) containing 10 mM HEPES (pH 7.4), 150 mM NaCl, 10%glycerol, 5 mM DTT, and 400 mM imidazole is used to elute the SYKprotein from the resin. The eluate is concentrated (5 mL) and furtherpurified on a Superdex 200 column (1.2 mL/min for 160 min, 10 mM HEPES(pH 7.4), 10 mM NaCl, 10 mM MgCl, 0.1 mM EDTA, and 0.25 mM TCEP). Thechromatographed fractions are run on SDS-PAGE and the requisitefractions are pooled and concentrated. Final delivery buffer is 10 mMHEPES (pH 7.4), 10 mM Methione, 150 mM NaCl, 10% glycerol, 5 mM DTT.

SYK inhibition is determined using a black 384 well plate format inbuffer containing 50 mM HEPES, 10 mM NaCl, 10 mM MgCl₂, 0.2 mM EDTA,0.01% EDA (Brij®35), 1 mM DTT, and 0.1 mg/ml BSA at pH 7.3. Each testcompound is prepared in DMSO using 2-fold serial dilutions for 11 datapoints, which are added to the buffer so that each dilution contains 3%DMSO. To each well is added 2 μL of 3 μM SFAM-KKKKEEIYFFFG-NH₂ (inbuffer), 2 μL of diluted test compound (3% DMSO in buffer), and 2 μL of2.4 nM SYK and 45 μM ATP (in buffer). The reaction mixture is incubatedat RT for 60 min, and quenched by adding 50 mM Hepes, 30 mM EDTA, 0.1%Triton X-100 (pH 7.3). To quantify the fluorescent-labeled substrate andproduct following reaction, the test plate is loaded on a CaliperLC-3000, which measures percent of conversion by microfluidic-basedseparation. Corresponding IC₅₀ values are calculated by non-linear curvefitting of the compound concentrations and percent of inhibition to thestandard IC₅₀ equation and reported as pIC₅₀, i.e., −log(IC₅₀), whereIC₅₀ is molar concentration.

EXAMPLES

The following examples are intended to be illustrative and non-limiting,and represent specific embodiments of the present invention.

¹H nuclear magnetic resonance (NMR) spectra were obtained for many ofthe compounds in the following examples. Characteristic chemical shifts(δ) are given in parts-per-million downfield from tetramethylsilaneusing conventional abbreviations for designation of major peaks,including s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), spt (septet) and br (broad). The mass spectra (m/z) wererecorded using either electrospray ionization (ESI) or atmosphericpressure chemical ionization (APCI). The following abbreviations areused for common solvents: CDCl₃ (deuterochloroform), DMSO-d₆(deuterodimethylsulfoxide), CD₃OD (deuteromethanol), and THF-d₈(deuterotetrahydrofuran). “Ammonia” refers to a concentrated solution ofammonia in water possessing a specific gravity of 0.88.

Where indicated, products of certain preparations and examples arepurified by mass-triggered HPLC (e.g., Pump: Waters™ 2525; MS: ZQ™;Software: MassLynx™) flash chromatography or preparative thin layerchromatography (TLC). Preparative HPLC is carried out using eitheracidic or basic conditions. Acid conditions are typically gradients inSolvent A (water with 0.05% TFA) and Solvent B (acetonitrile with 0.035%TFA); basic conditions are typically gradients in Solvent A (10 mMNH₄HCO₃ in water) and Solvent B (10 mM NH₄HCO₃ in 20/80 (v/v)water/acetonitrile). The mentioned preparative HPLC conditions useacidic conditions unless indicated as basic. Preparative TLC istypically carried out on silica gel 60 F₂₅₄ plates. After isolation bychromatography, the solvent is removed and the product is obtained bydrying in a centrifugal evaporator (e.g., GeneVac™) rotary evaporator,evacuated flask, lyophilizer, etc. Reactions in an inert (e.g.,nitrogen) or reactive (e.g., H₂) atmosphere are typically carried out ata pressure of about 1 atmosphere (14.7 psi) or greater.

PREPARATION 1: 3-(Difluoromethyl)-5-(tributylstannyl)isothiazole

STEP A: Isothiazol-3-ylmethanol

To a stirred suspension of isothiazole-3-carboxylic acid (500 mg, 3.87mmol) in THF (10 mL) was added BH₃.THF (15.49 mL, 15.49 mmol) dropwiseat 0° C. The reaction mixture was stirred at 70° C. for 1 h, then cooledto 0° C., quenched with MeOH, and concentrated in vacuo. Water was addedto the residue and the mixture was extracted with EtOAc. The extractswere dried over anhydrous sodium sulfate, filtered, and concentrated invacuo. The resulting residue was purified by silica gel chromatography(Biotage™ Flash 60 column) eluting with hexane/EtOAc (1:1) to give thetitle compound as a yellow oil (149.9 mg, 33.6%). ¹H NMR (500 MHz,CDCl₃) δ ppm 2.45-2.76 (m, 1H), 4.86 (s, 2H), 7.22 (d, J=4.64 Hz, 1H),8.67 (d, J=4.64 Hz, 1H).

STEP B: Isothiazole-3-carbaldehyde

To a stirred suspension of isothiazol-3-ylmethanol (140 mg, 1.23 mmol)in EtOAc (5.0 mL) was added manganese dioxide (700 mg, 8.05 mmol). Thereaction mixture was stirred at room temperature overnight. The mixturewas subsequently filtered through Celite and the filtrate wasconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (Biotage™ Flash 60 column) eluting with hexane/EtOAc(4:1) to give the title compound as colorless oil (39.8 mg, 29%). ¹H NMR(500 MHz, CDCl₃) δ ppm 7.82 (d, J=4.64 Hz, 1H), 8.74 (d, J=4.60 Hz, 1H),10.08 (s, 1H).

STEP C: 3-(Difluoromethyl)isothiazole

To a stirred solution of isothiazole-3-carbaldehyde (77.6 mg, 0.686mmol) in CH₂Cl₂ (5.0 mL) was added N,N-diethylaminosulfur trifluoride(0.272 mL, 2.06 mmol) dropwise at 0° C. The reaction mixture was stirredat 0° C. for 1 h, quenched with saturated aq NaHCO₃, and extracted withEtOAc. The extracts were dried over anhydrous sodium sulfate, passedthrough a short pad of silica gel (eluting with EtOAc) and evaporated invacuo to give the title compound, which was used without furtherpurification.

STEP D: 3-(Difluoromethyl)-5-(tributylstannyl)isothiazole

To a cold (−78° C.) solution of 3-(difluoromethyl)isothiazole (93 mg,0.688 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.473mL, 0.757 mmol) dropwise. The reaction mixture was stirred for 60minutes at −78° C. A solution of tributylchlorostannane (0.223 mL, 0.826mmol) in anhydrous THF (0.5 mL) was added and the reaction mixture wasstirred for 30 minutes at −78° C. The solution was subsequently allowedto warm to room temperature over a period of about one hour. Saturatedaq NaHCO₃ was added, and the aqueous phase was extracted with EtOAc. Theorganic phases were combined, dried over anhydrous sodium sulfate,passed through a short pad of silica gel (eluting with EtOAc) andevaporated in vacuo to give the title compound, which was used withoutfurther purification.

PREPARATION 2: 5-(Tributylstannyl)-3-vinylisothiazole

STEP A: 3-Vinylisothiazole

A solution of 3-bromoisothiazole (100 mg, 0.610 mmol),tributyl(vinyl)stannane (580 mg, 1.829 mmol),tetrakis(triphenylphosphine)palladium(0) (352 mg, 0.305 mmol) in toluene(2 mL) was heated to 120° C. for 45 minutes via microwave irradiation.The reaction mixture was poured into water and was extracted with EtOAc.The extracts were dried over Na₂SO, and concentrated in vacuo. Theresidue was purified by silica gel chromatography (Flash 60 column)eluting with hexane/EtOAc (19:1) to give the title compound as acolorless oil (26.3 mg, 39%). ¹H NMR (500 MHz, CDCl₃) δ ppm 5.54 (d,J=10.25 Hz, 1H), 5.98 (d, J=18.55 Hz, 1H), 6.86-6.95 (m, 1H), 7.37 (d,J=4.88 Hz, 1H), 8.59 (d, J=4.90 Hz, 1H).

STEP B: 5-(Tributylstannyl)-3-vinylisothiazole

To a cold (−78° C.) solution of 3-vinylisothiazole (300 mg, 2.70 mmol)in anhydrous THF (6.0 mL) was added n-butyllithium (1.855 mL, 2.97 mmol)dropwise. After stirring the reaction mixture for 60 minutes at −78° C.,a solution of tributylchlorostannane (0.873 mL, 3.24 mmol) in anhydrousTHF (1.5 mL) was added. The reaction mixture was stirred for 30 minutesat −78° C. and then allowed to warm to room temperature over a 1 hourperiod. Saturated aqueous sodium bicarbonate was added and the aqueousphase was extracted with EtOAc. The organic phases were combined, driedover anhydrous sodium sulfate, filtered, and evaporated in vacuo. Theresidue was purified by silica gel chromatography (Flash 60 column)eluting with hexane/EtOAc (19:1) to give the title compound as a paleyellow oil (472.8 mg, 44%). ¹H NMR (500 MHz, CDCl₃) δ ppm 0.90 (t,J=7.32 Hz, 9H), 1.13-1.18 (m, 6H), 1.34 (sextet, J=7.42 Hz, 6H),1.52-1.61 (m, 6H), 5.50 (dd, J=11.23, 0.98 Hz, 1H), 6.00 (dd, J=17.60,0.98 Hz, 1H), 6.96 (dd, J=17.57, 11.23 Hz, 1H), 7.33 (s, 1H).

PREPARATION 3: 5-(Tributylstannyl)isothiazole

To a cold (−78° C.) solution of isothiazole (100 mg, 1.175 mmol) inanhydrous THF (2.0 mL) was added n-butyllithium (0.808 mL, 1.292 mmol)dropwise. The reaction mixture was stirred for 60 minutes at −78° C. Asolution of tributylchlorostannane (0.380 mL, 1.410 mmol) in anhydrousTHF (0.5 mL) was added, and the reaction mixture was stirred for 30minutes at −78° C. The solution was allowed to warm to room temperatureover a 1 hour period. Saturated aqueous sodium bicarbonate was added andthe aqueous phase was extracted with EtOAc. The combined organic phasewas dried over anhydrous sodium sulfate, filtered, and evaporated invacuo. The residue was purified by silica gel chromatography (Flash 60column) eluting with hexane/EtOAc (19:1) to give the title compound as apale yellow oil (139.3 mg, 32%). ¹H NMR (500 MHz, CDCl₃) δ ppm 0.90 (t,J=7.32 Hz, 9H), 1.14-1.20 (m, 6H), 1.28-1.39 (m, 6H), 1.51-1.62 (m, 6H),7.27-7.32 (m, 1H), 8.66 (d, J=1.46 Hz, 1H).

PREPARATION 4: 3-Cyclopropyl-5-(tributylstannyl)isothiazole

STEP A: 3-cyclopropyl-5-iodoisothiazole

To a water (1.4 mL) and ice (5.0 cc) suspension was added3-cyclopropylisothiazol-5-amine (500 mg, 3.57 mmol) followed byconcentrated sulfuric acid (1.4 mL). A solution of sodium nitrite (258mg, 3.74 mmol) in water (5.0 mL) was added dropwise at 0° C., and themixture was stirred at 0° C. for 1 hour. Next, a solution of potassiumiodide (622 mg, 3.74 mmol) in water (3.5 mL) was added dropwise at 0°C., and the mixture was heated at 80° C. for 1 hour. Ethyl acetate at 0°C. was added and the mixture was neutralized with potassium carbonate.The organic layer was separated, dried over magnesium sulfate,concentrated under reduced pressure, and purified by silica gelchromatography (Flash 60 column) eluting with hexane/EtOAc (19:1) togive the title compound as green oil (356.5 mg, 40%). ¹H NMR (500 MHz,CDCl₃) δ ppm 0.92-0.98 (m, 2H), 0.98-1.04 (m, 2H), 2.13-2.20 (m, 1H),7.06 (s, 1H).

STEP B: 3-Cyclopropyl-5-(tributylstannyl)isothiazole

To a cold (−78° C.) solution of 3-cyclopropyl-5-iodoisothiazole (100 mg,0.398 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.299mL, 0.478 mmol) dropwise. The reaction mixture was stirred for 60minutes at −78° C. A solution of tributylchlorostannane (0.129 mL, 0.478mmol) in anhydrous THF (2.0 mL) was added to the reaction mixture, whichwas stirred for 30 minutes −78° C. and subsequently allowed to warm toambient temperature over a 1 hour period. Saturated aqueous sodiumbicarbonate was added to the reaction mixture. The aqueous phase wasextracted with EtOAc and the combined organic phase was dried overanhydrous sodium sulfate, filtered, and evaporated in vacuo. The residuewas purified by silica gel chromatography (Flash 60 column) eluting withhexane/EtOAc (19:1) to give the title compound as a colorless oil (142.8mg, 87%). ¹H NMR (500 MHz, CDCl₃) δ ppm 0.85-0.93 (m, 9H), 0.95-1.05 (m,4H), 1.09-1.17 (m, 6H), 1.28-1.38 (m, 6H), 1.47-1.61 (m, 6H), 2.20-2.29(m, 1H), 6.93 (s, 1H).

PREPARATION 5: 3-Methyl-5-(tributylstannyl)isothiazole

To a cold (−78° C.) solution of 3-methylisothiazole (100 mg, 1.0 mmol)in anhydrous THF (2.0 mL) was added n-butyllithium (0.693 mL, 1.1 mmol)dropwise. After stirring for 60 minutes at −78° C., a solution oftributylchlorostannane (0.326 mL, 1.210 mmol) in anhydrous THF (0.5 mL)was added to the reaction mixture. The reaction mixture was stirred for30 minutes at −78° C. and then allowed to warm to RT over a 2 to 3 hourperiod. Saturated aq NaHCO₃ was added and the aqueous phase wasextracted with EtOAc (3×50 mL). The combined organic phase was driedover anhydrous Na₂SO₄, filtered, and evaporated in vacuo. The residuewas purified by silica gel chromatography (Flash 60 column) eluting withhexane/EtOAc (9:1) to give the title compound. ¹H NMR (500 MHz, CDCl₃) δppm 0.86-0.94 (m, 9H), 1.05-1.21 (m, 6H), 1.26-1.38 (m, 6H), 1.44-1.65(m, 6H), 2.56 (s, 3H), 6.97-7.04 (m, 1H).

PREPARATION 6:3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole

To a cooled (−25° C.) solution of 5-iodo-3-methylisothiazole (59.5 g,264 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.2g, 270 mmol) in anhydrous THF (300 mL) was added dropwise 1.3 Misopropylmagnesium lithium chloride in THF (218 mL, 283 mmol) at a ratewhich maintained the temperature at −15° C. to −25° C. The reactionmixture was stirred at −10° C. for 5 minutes after the addition wascompleted. HPLC analysis indicated that the starting material wasconsumed. A solution of acetic acid (16.19 mL, 283 mmol) in THF (40 mL)was added slowly to the reaction solution at 0° C. Hexanes (250 mL) andMTBE (150 mL) were sequentially added to the reaction mixture. A solidprecipitate was formed, which was filtered off by passing the reactionmixture through a pad of Celite. The filtrate was concentrated viarotary evaporation to afford an oil residue, which was dispersed in MTBE(500 mL) through vigorous stirring. Additional precipitate was formed,which was filtered off using a pad of Celite. The filtrate was againconcentrated to an oil, and MTBE (200 mL) was added, which formedadditional solid precipitate that was filtered off using a pad ofCelite. The process was repeated two more times until no more solid wasformed when MTBE was added to the oil residue. The oil was dried in arotary evaporator under high vacuum overnight with a bath temperature of20° C., which afforded the title compound as an oil (49.55 g, 83%). ¹HNMR (400 MHz, CDCl₃) δ ppm 1.37 (s, 12H), 2.56 (s, 3H), 7.41 (s, 1H).

PREPARATION 7: Thieno[2,3-c]pyridin-2-ylboronic acid

To a cold (−78° C.) solution of thieno[2,3-c]pyridine (2.040 g, 15.09mmol) in anhydrous THF (50 mL) was added n-butyllithium (6.64 mL, 16.60mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78°C. A solution of triisopropyl borate (4.16 mL, 18.11 mmol) was added andthe reaction mixture was stirred for 30 minutes at −78° C. The solutionwas allowed to warm to room temperature over a 2 hour period. TLC showedthe reaction was complete. Aqueous HCl (1N, 1000 mL) and DCM (500 mL)were added to the reaction mixture. The aqueous and organic layers wereseparated. The aqueous layer was concentrated to a volume of 500 mL anda solid precipitate was filtered and dried to give the title compound asoff-white, needle-shaped crystals (2.4 g, 74%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.24 (s, 1H), 8.41 (d, J=4.80 Hz, 1H), 8.66 (d, J=6.32Hz, 1H), 9.10 (br s, 2H), 9.72 (br s, 1H).

PREPARATION 8: 2-(Tributylstannyl)thieno[2,3-c]pyridine

To a cold (−78° C.) solution of thieno[2,3-c]pyridine (524 mg, 3.88mmol) in anhydrous THF (50 mL) was added n-butyllithium (2.66 mL, 4.26mmol) dropwise. The mixture was stirred for 60 minutes at −78° C. Asolution of tributylchlorostannane (1.254 mL, 4.65 mmol) in anhydrousTHF (10 mL) was added, and the reaction mixture was stirred for 30minutes at −78° C. The solution was allowed to warm to room temperatureover a period of 2 to 3 hours. Saturated aqueous sodium bicarbonate wasadded. The aqueous phase was extracted with diethyl ether (3×200 mL).The combined organic phase was dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo. The crude product was purified bysilica gel column chromatography, eluting with a gradient of 10-50%EtOAc and hexane over a period of 60 minutes. The desired fractions werecollected to give the title compound as a clear oil (1.1 g, 67%). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.86 (t, J=7.32 Hz, 9H), 1.08-1.38 (m, 12H),1.45-1.71 (m, 6H), 7.59 (s, 1H), 7.76-7.93 (m, 1H), 8.41 (s, 1H), 9.23(s, 1H).

PREPARATION 9:2-(5-Fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of thiophene (252 mg, 2.99 mmol) in THF (3.5 mL) at −78°C. was added n-butyllithium (2.5M, 1.3 mL, 3.2 mmol) dropwise to keepthe temperature below −70° C. The solution was stirred for 40 minutes at−78° C. A solution of N-fluorobenzenesulfonimide (987 mg, 3.1 mmol) inTHF (5 mL) was added over a period of 20 minutes. The temperature of themixture was allowed to rise to −10° C. and was subsequently cooled to−78° C. To the mixture was added n-butyllithium (2.5M, 1.3 mL, 3.2 mmol)and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (580 mg, 3.1mmol) in THF (2 mL). The reaction was allowed to continue at −78° C. for30 min and then quenched with saturated aqueous ammonium chloride (10mL). The organic layer was separated and the aqueous phase was extractedwith EtOAc (3×15 mL). The organic layers were combined and dried oversodium sulfate. After removal of solvent, the residue was purified byflash chromatography (petroleum ether/ethyl acetate=20:1) to give thetitle compound (143 mg, 21%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.32 (s,12H), 6.55 (d, J=3.6 Hz, 1H), 7.27 (d, J=3.6 Hz, 1H).

PREPARATION 10: 2-(Tributylstannyl)thieno[2,3-b]pyridine

To a cold (−78° C.) solution of thieno[2,3-b]pyridine (2.000 g, 14.79mmol) in anhydrous THF (50 mL) was added n-butyllithium (10.17 mL, 16.27mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78°C. A solution of tributylchlorostannane (4.79 mL, 17.75 mmol) inanhydrous THF (10 mL) was added and the reaction mixture was stirred for30 minutes at −78° C. The solution was allowed to warm to roomtemperature over a period of 2 to 3 hours. Saturated aqueous sodiumbicarbonate was added. The aqueous phase was extracted with ether (3×200mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and evaporated in vacuo. The crude product waspurified by silica gel column chromatography, eluting with a gradient of10-50% EtOAc and hexane over a period of 60 minutes. The desiredfractions were collected and the solvent removed in vacuo to give thetitle compound (4.5 g, 72%)¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.87 (t,J=7.32 Hz, 9H), 1.13-1.20 (m, 6H), 1.32 (dq, J=14.64, 7.32 Hz, 6H),1.52-1.64 (m, 6H), 7.34-7.42 (m, 1H), 7.51 (s, 1H), 8.25 (dd, J=7.81,1.46 Hz, 1H), 8.50 (dd, J=4.39, 1.46 Hz, 1H).

PREPARATION 11: 2-(Tributylstannyl)thieno[3,2-c]pyridine

To a cold (−78° C.) solution of thieno[3,2-c]pyridine (2.000 g, 14.79mmol) in anhydrous THF (50 mL) was added n-butyllithium (10.17 mL, 16.27mmol) dropwise. The reaction mixture was stirred at −78° C. for 60minutes. A solution of tributylchlorostannane (4.79 mL, 17.75 mmol) inanhydrous THF (10 mL) was added. The reaction mixture was stirred at−78° C. for 30 minutes and the solution was allowed to warm to roomtemperature over a period of 2 to 3 hours. Saturated aqueous NaHCO₃ wasadded. The aqueous phase was extracted with ether (3×200 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo. The crude product was purified bysilica gel column chromatography, eluting with a gradient of 10-50%EtOAc and hexane over a period of 60 minutes. The desired fractions werecollected to give the title compound as a clear oil (4.2 g, 67%). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.79-0.94 (m, 9H), 1.10-1.24 (m, 6H), 1.32(sextet, J=7.32 Hz, 6H), 1.51-1.66 (m, 6H), 7.63-7.70 (m, 1H), 8.04 (d,J=5.37 Hz, 1H), 8.35 (d, J=5.86 Hz, 1H), 9.16 (d, J=0.98 Hz, 1H).

PREPARATION 12: 5-Cyanobenzo[b]thiophen-2-ylboronic acid

To a cold (−78° C.) solution of benzo[b]thiophene-5-carbonitrile (276mg, 1.734 mmol) in anhydrous THF (5 mL) was added n-butyllithium (0.763mL, 1.907 mmol) dropwise. The reaction mixture was stirred at −78° C.for 60 minutes. Next, a solution of triisopropyl borate (0.478 mL, 2.080mmol) was added. The reaction mixture was stirred for 30 minutesstirring at −78° C. and then was allowed to warm to room temperatureover a 2 hour period. Solvent was removed to give the title compound,which was used without purification or work up.

PREPARATION 13: 4-Fluorobenzo[b]thiophen-2-ylboronic acid

STEP A: 4-Fluorobenzo[b]thiophene

A mixture of 4-fluorobenzo[b]thiophene-2-carboxylic acid (200 mg, 1.019mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.457 mL, 3.06 mmol) inDMA (1 mL) was heated at 200° C. for 1 hour. The reaction mixture wasallowed to cool and was poured into water (100 mL). The product wasextracted with hexane (2×20 mL) and washed with 1N HCl (100 mL) and 1NNaOH (50 mL). The organic layers were combined, dried over Na₂SO₄ andthe solvent was removed in vacuo to give the title compound as a yellowoil, which was used without further purification.

STEP B: 4-Fluorobenzo[b]thiophen-2-ylboronic acid

To a cold (−78° C.) solution of 4-fluorobenzo[b]thiophene (80.4 mg,0.528 mmol) in anhydrous THF (1 mL) was added n-butyllithium (0.363 mL,0.581 mmol) dropwise. The reaction mixture was stirred at −78° C. for 60minutes. A solution of triisopropyl borate (0.146 mL, 0.634 mmol) wasadded. The reaction mixture was stirred at −78° C. for 30 minutes andwas then allowed to warm to room temperature over a 2 hour period. TLCshowed completion of reaction. 1N HCl (100 mL) and DCM (50 mL) wereadded to the reaction mixture. The aqueous and organic layers wereseparated. The aqueous layer was concentrated to 50 mL, yielding a solidprecipitate that was filtered and dried to give the title compound asoff-white, needle-shaped crystals. The product was used without furtherpurification.

PREPARATION 14: Thieno[3,2-b]pyridin-2-ylboronic acid hydrochloride

STEP A: Thieno[3,2-b]pyridine

A solution of 7-chlorothieno[3,2-b]pyridine (500 mg, 2.95 mmol) and zinc(193 mg, 2.95 mmol) in acetic acid (5 mL) was stirred at roomtemperature for 3 days, followed by stirring at 50° C. for 5 hours. Thesolvent was removed in vacuo and the residue was dissolved in DCM (200mL) and extracted with 1N NaOH (500 mL). The aqueous layer was washedagain with DCM (2×200 mL). The organic layers were combined, dried overNa₂SO₄, and the solvent was removed in vacuo to yield the title compoundas a yellow oil, which was used without further purification. ESI-MS m/z[M+H]⁺calc'd for C₇H₅NS, 136. found, 136.

STEP B: Thieno[3,2-b]pyridin-2-ylboronic acid hydrochloride

To a cold (−78° C.) solution of thieno[3,2-b]pyridine (404 mg, 2.99mmol) in anhydrous THF (1 mL) was added n-butyllithium (2.055 mL, 3.29mmol) dropwise. The reaction mixture was stirred at −78° C. for 60minutes, after which a solution of triisopropyl borate (0.825 mL, 3.59mmol) was added. The reaction mixture was stirred at −78° C. for 30minutes and was then allowed to warm to room temperature over a periodof 2 hours. UPLC showed completion of reaction. The solvent was removedand DCM (50 mL) and aqueous 1N HCl (50 mL) were added to the residue.The organic layer was separated, and the aqueous layer was collected andconcentrated to yield an HCl salt of the title compound as a yellowsolid, which was used without further purification.

PREPARATION 15:2-(4-Fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

STEP A: 3-Fluorothiophene

To a single neck round bottom flask containing3-fluorothiophene-2-carboxylic acid (1.68 g, 11.50 mmol) dissolved inquinoline (12 mL) was added copper chromite (1.789 g, 5.75 mmol). Theround bottom flask was connected to a distillation unit fitted with athermometer and a receiving flask maintained at about 0° C. The reactionmixture was initially heated at 150° C. for 1 hour and then at 185° C.Volatile 3-fluorothiophene started slowly distilling into the receivingflask as a colorless liquid. After 20 minutes, a slight vacuum wasapplied to ensure complete distillation of 3-fluorothiophene, whiletaking care to ensure that no quinoline was distilled into the receivingflask. Once the distillation was complete, the receiving flask wassealed and the title compound was stored in a refrigerator until it wasused (580 mg, 99%). ¹H NMR (400 MHz, CDCl₃) δ ppm 6.72 (dt, J=3.47, 1.29Hz, 1H), 6.81-6.92 (m, 1H), 7.19 (dt, J=5.43, 3.35 Hz, 1H).

STEP B:2-(4-Fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a mixture of [Ir(μ-OMe(COD)] (50 mg, 0.015 mmol, 3 mol %) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.292 g, 9.79 mmol) was added asolution of 4,4′-di-tert-butyl-2,2′-bipyridine (0.039 g, 0.147 mmol) inn-hexane (3 mL). The reaction mixture was stirred for 1 minute and thenadded to a vessel containing 3-fluorothiophene (0.5 g, 4.90 mmol)dissolved in hexane (3 mL). The mixture was allowed to react at roomtemperature for 1 hour. The mixture was subsequently evaporated and usedwithout further work up.

PREPARATION 16: 1-Methyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole

STEP A: (E)-1-((3-Bromothiophen-2-yl)methylene)-2-(diphenylmethylene)hydrazine

3-Bromothiophene-2-carbaldehyde (8.0 g, 41.9 mmol) and(diphenylmethylene)hydrazine (9.45 g, 48.2 mmol) were dissolved inethanol (60 mL) and the solution was heated at 80° C. overnight.Volatiles from the reaction mixture were removed via rotary evaporationand the crude product was purified by normal phase silica gelchromatography (ISCO-Combiflash) eluting with a gradient of 0-30% hexaneand EtOAc. The pure fractions were combined and evaporated to give thetitle compound as a mixture of cis/trans isomers (15.0 g, 97%). ESI-MSm/z [M+H]⁺calc'd for C₁₈H₁₃BrN₂S, 370. found, 370.

STEP B:(E)-1-(Diphenylmethylene)-2-((3-(2-(diphenylmethylene)hydrazinyl)thiophen-2-yl)methylene)hydrazine

To a mixture of(E)-1-((3-bromothiophen-2-yl)methylene)-2-(diphenylmethylene)hydrazine(15 g, 40.6 mmol, including its Z isomer) and(diphenylmethylene)hydrazine (9.57 g, 48.7 mmol) in toluene (125 mL) wasadded palladium(II) acetate (0.120 g, 2.031 mmol),1,1′-bis(diphenylphosphino)ferrocene (2.252 g, 4.06 mmol) and Cs₂CO₃(26.5 g, 81 mmol). The reaction mixture was stirred at 85° C. for 14hours and was subsequently diluted with toluene (25 mL) and filtered toremove undissolved solids. The filtrate was purified by flash columnchromatography. The pure product fractions were evaporated to give thetitle compound (15.5 g, 79%). ESI-MS m/z [M+H]⁺calc'd for C₃₁H₂₄N₄S,485. found, 485.

STEP C: 1H-thieno[3,2-c]pyrazole

To a solution of(E)-1-(diphenylmethylene)-2-((3-(2-(diphenylmethylene)hydrazinyl)thiophen-2-yl)methylene)hydrazine(15 g, 31.0 mmol) in EtOH (125 mL) was added concentrated HCl (50 mL).The reaction mixture was heated at 80° C. for 2 hours. The mixture wasthen basified with saturated aqueous NaHCO₃ (20 mL) and solid NaHCO₃ topH 8-9 and the aqueous solution was extracted with EtOAc (2×250 mL). Theorganic layers were combined, dried over sodium sulfate, and evaporated.The resulting mixture was purified by silica gel column chromatography,eluting with a gradient of 0-20% dichloromethane and methanol. The pureproduct fractions were combined and evaporated to give the titlecompound (2.8 g, 73%). ESI-MS m/z [M+H]⁺ calc'd for C₅H₄N₂S, 125. found,125.

STEP D: (a) 1-Methyl-1H-thieno[3,2-c]pyrazole and (b)2-methyl-2H-thieno[3,2-c]pyrazole

1H-thieno[3,2-c]pyrazole (2500 mg, 20.13 mmol) was dissolved in THF (45mL) under nitrogen and cooled to 0° C. in an ice bath. Sodium hydride(966 mg, 24.16 mmol) was slowly added. After 20 minutes, iodomethane(1.511 mL, 24.16 mmol) was added dropwise, and the mixture was allowedto react at room temperature for an hour. The reaction was subsequentlyquenched with water (20 mL) and extracted with EtOAc (2×60 mL). Theorganic layers were combined, dried over sodium sulfate, and evaporated.The resulting gummy liquid was purified by silica gel column (80 g)chromatography, eluting with a gradient of 0-100% hexane and EtOAc andyielding two clean separate product fractions. The fractionscorresponding to one of the two products were combined and the solventevaporated to give title compound (a) as a light green liquid (1.45 g,53%). ¹H NMR (400 MHz, CDCl₃) δ ppm 4.03 (s, 3H), 6.90 (dd, J=5.31, 0.76Hz, 1H), 7.38 (d, J=5.31 Hz, 1H), 7.65 (s, 1H). ESI-MS m/z [M+H]⁺ calc'dfor C₆H₆N₂S, 139. found, 139. The fractions corresponding to the secondof the two products were combined and the solvent evaporated to givetitle compound (b) as a light green liquid (1.32 g, 47%). ESI-MS m/z[M+H]⁺ calc'd for C₆H₆N₂S, 139. found, 139.

STEP E: 1-Methyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole

To a cold (−78° C.) mixture of 1-methyl-1H-thieno[3,2-c]pyrazole (200mg, 1.447 mmol) in THF (10 mL) was added n-butyllithium (0.637 mL, 1.592mmol) dropwise under a nitrogen atmosphere. The reaction mixture wasstirred at −78° C. for 60 minutes. Tributylchlorostannane (0.471 mL,1.737 mmol) was added, and the reaction mixture was stirred at −78° C.for 60 minutes and then warmed to room temperature over a period of 2hours. The reaction was quenched with brine (20 mL) and extracted withethyl acetate (2×30 mL). The organic layers were combined, dried oversodium sulfate, concentrated, and purified via flash chromatography,eluting with 20% EtOAc and hexane to give the title compound as a clearoil (420 mg, 68%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.76-0.99 (m, 9 H),0.99-1.22 (m, 6H), 1.22-1.51 (m, 6H), 1.51-1.72 (m, 6H), 4.02 (s, 3H),6.87 (d, J=0.51 Hz, 1H), 7.58 (s, 1H).

PREPARATION 17: (a) 1,3-Dimethyl-1H-thieno[3,2-c]pyrazole and (b)2,3-dimethyl-2H-thieno[3,2-c]pyrazole

STEP A: (E)-1-(1-(3-Bromothiophen-2-yl)ethylidene)-2-(diphenylmethylene)hydrazine

1-(3-Bromothiophen-2-yl)ethanone (8.0 g, 39.0 mmol) and(diphenylmethylene)hydrazine (8.42 g, 42.9 mmol) were dissolved inethanol (75 mL). The reaction mixture was heated in an oil bath at 80°C. for 16 hours. Following reaction, the volatiles were evaporated, andthe condensed mixture was purified via silica gel column chromatography,eluting with a gradient of 0-100% hexane and EtOAc. The pure fractionswere combined and evaporated to give the title compound as a yellowsolid (12.5 g, 84%). ESI-MS m/z [M+H]⁺calc'd for C₁₉H₁₅BrN₂S, 384.found, 384.

STEP B:(E)-1-(Diphenylmethylene)-2-(1-(3-(2-(diphenylmethylene)hydrazinyl)thiophen-2-yl)ethylidene)hydrazine

To a mixture of(E)-1-(1-(3-bromothiophen-2-yl)ethylidene)-2-(diphenylmethylene)hydrazine(12.5 g, 32.6 mmol, including its Z isomer) and(diphenylmethylene)hydrazine (7.68 g, 39.1 mmol) in toluene (25 mL) wasadded palladium(II) acetate (0.385 g, 6.52 mmol),1,1′-bis(diphenylphosphino)ferrocene (1.808 g, 3.26 mmol) and Cs₂CO₃(21.25 g, 65.2 mmol). The reaction mixture was heated at 80° C. for 14hours. The mixture was subsequently diluted with toluene (25 mL) andfiltered to remove solids. The filtrate was evaporated andchromatographed using a gradient of 0-100% hexane and EtOAc. The pureproduct fractions were combined and evaporated to give the titlecompound (12.5 g, 77%). ESI-MS m/z [M+H]⁺calc'd for C₃₂H₂₆N₄S, 499.found, 499.

STEP C: 3-Methyl-1H-thieno[3,2-c]pyrazole

To a mixture of(E)-1-(diphenylmethylene)-2-(1-(3-(2-(diphenylmethylene)hydrazinyl)thiophen-2-yl)ethylidene)hydrazine(12.5 g, 25.07 mmol) in EtOH (75 mL) was added concentrated HCl (40 mL).The reaction mixture was heated at 80° C. for 2 hours, then basifiedwith saturated aqueous NaHCO₃ (50 mL) and solid NaHCO₃ to pH 8-9. Thereaction mixture was extracted with EtOAc (2×250 mL). The organic layerswere combined, dried over sodium sulfate, and evaporated. The resultingmixture was purified by silica gel column chromatography, eluting with agradient of 0-20% dichloromethane and methanol. The pure productfractions were combined and evaporated to give the title compound as atan solid (2.6 g, 75%). ¹H NMR (400 MHz, CDCl₃) δ ppm 2.42-2.57 (m, 3H),6.97 (d, J=5.05 Hz, 1H), 7.40 (d, J=5.31 Hz, 1H), 9.04 (br s, 1H).ESI-MS m/z [M+H]⁺calc'd for C₆H₆N₂S, 139. found, 139.

STEP D: (a) 1,3-Dimethyl-1H-thieno[3,2-c]pyrazole and (b)2,3-dimethyl-2H-thieno[3,2-c]pyrazole

3-Methyl-1H-thieno[3,2-c]pyrazole (2 g, 14.47 mmol) was dissolved in THF(45 mL) under nitrogen and was cooled to 0° C. in an ice bath. Sodiumhydride (695 mg, 17.37 mmol) was slowly added. After 20 minutes,iodomethane (1.086 mL, 17.37 mmol) was added dropwise. The mixture wasallowed to react at room temperature for 1 hour. The reaction mixturewas quenched with water (20 mL) and extracted with EtOAc (2×60 mL). Theorganic layers were combined, dried over sodium sulfate, and evaporated.The resulting gummy liquid was purified by silica gel column (80 g)chromatography, eluting with a gradient of 0-100% hexane and EtOAc andyielding two clean separate product fractions. The fractionscorresponding to one of the two products were combined and the solventevaporated to give the title compound (a) as black liquid (1.0 g, 45%).¹H NMR (400 MHz, CDCl₃) δ ppm 2.43 (s, 3H), 3.95 (s, 3H), 6.84 (d,J=5.31 Hz, 1H), 7.34 (d, J=5.31 Hz, 1H). ESI-MS m/z [M+H]⁺calc'd forC₇H₈N₂S, 153. found, 153. The fractions corresponding to the second ofthe two products were combined and the solvent evaporated to give titlecompound (b) as a black liquid (1.354 g, 62%). ¹H NMR (400 MHz, CDCl₃) δppm 2.48 (s, 3H), 3.97 (s, 3H), 7.03 (d, J=5.31 Hz, 1H), 7.28 (d, J=5.31Hz, 1H). ESI-MS m/z [M+H]⁺calc'd for C₇H₈N₂S, 153. found, 153.

PREPARATION 18:1,3-Dimethyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole

To a cold (−78° C.) mixture of 1,3-dimethyl-1H-thieno[3,2-c]pyrazole(400 mg, 2.63 mmol) and THF (15 mL) under a nitrogen atmosphere wasadded n-butyllithium (1.156 mL, 2.89 mmol) dropwise. The reactionmixture was stirred at −78° C. for 60 minutes. Tributylchlorostannane(0.855 mL, 3.15 mmol) was added, and the reaction mixture was stirred at−78° C. for 60 minutes and then warmed to room temperature with stirringover a period of 1 hour. The reaction mixture was quenched with brine(15 mL) and extracted with EtOAc (2×25 mL). The organic layers werecombined, dried over sodium sulfate, and evaporated. The resultingresidue was purified by normal-phase silica gel column (80 g)chromatography, eluting with a gradient of 0-100% hexane and EtOAc. Thepure product fractions were combined and evaporated to give the titlecompound as a clear oil (1.060 g, 91%). ¹H NMR (400 MHz, CDCl₃) δ ppm0.77-0.98 (m, 9H), 1.04-1.20 (m, 6H), 1.25-1.47 (m, 6H), 1.49-1.70 (m,6H), 2.41 (s, 3H), 3.94 (s, 3H), 6.82 (s, 1H). ESI-MS m/z [M+H]⁺calc'dfor C₁₉H₃₄N₂SSn, 443. found, 443.

PREPARATION 19:2,3-Dimethyl-5-(tributylstannyl)-2H-thieno[3,2-c]pyrazole

To a cold (−78° C.) mixture of 2,3-dimethyl-2H-thieno[3,2-c]pyrazole(400 mg, 2.63 mmol) and THF (15 mL) under a nitrogen atmosphere wasadded n-butyllithium (1.156 mL, 2.89 mmol) dropwise. The reactionmixture was stirred at −78° C. for 60 minutes. Tributylchlorostannane(0.855 mL, 3.15 mmol) was added, and the reaction mixture was stirred at−78° C. for 60 minutes and then warmed to room temperature with stirringover a period of 1 hour. The reaction mixture was quenched with brine(15 mL) and extracted with EtOAc (2×25 mL). The organic layers werecombined, dried over sodium sulfate, and evaporated. The resultingresidue was purified by silica gel column (80 g) chromatography, elutingwith a gradient of 0-100% hexane and EtOAc. The pure product fractionswere combined and evaporated to give the title compound as a gray solid(1.060 g, 2.402 mmol, 91%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.78-0.99 (m,9H), 1.06-1.22 (m, 6H), 1.23-1.46 (m, 6H), 1.48-1.70 (m, 6H), 2.46 (s,3H), 3.96 (s, 3H), 7.03 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₁₉H₃₄N₂SSn, 443. found, 443.

PREPARATION 20:7-(Tributylstannyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine

STEP A: 4-Iodo-1H-pyrrole-2-carbaldehyde

To a cold (−78° C.) solution of 1H-pyrrole-2-carbaldehyde (7.0 g, 73.6mmol) and THF (50 mL) was added 1-iodopyrrolidine-2,5-dione (19.87 g, 88mmol) portion wise over a period of 20 minutes. The temperature of themixture was maintained at −78° C. for 2 hours. The reaction wassubsequently quenched with water (20 mL) and hexanes (100 mL) and themixture was allowed warm to room temperature. The organic and aqueouslayers were separated. The aqueous layer was extracted with hexanes (100mL). The organic layers were combined, dried over sodium sulfate, andevaporated to give the title compound (14 g, 86%). ESI-MS m/z[M+H]⁺calc'd for C₅H₄INO, 221. found, 221.

STEP B: 1-(2-Hydroxyethyl)-4-iodo-1I-pyrrole-2-carbaldehyde

To a solution of 4-iodo-1H-pyrrole-2-carbaldehyde (5 g, 22.62 mmol) anddioxane (25 mL) was added KOH (3.81 g, 67.9 mmol), followed by2-bromoethanol (3.31 mL, 45.2 mmol). The mixture was allowed to react at60° C. for 16 hours and was then cooled to room temperature. The pH wasadjusted to −6 by the addition of acetic acid. The reaction mixture wasthen concentrated in vacuo to give a residue, which was partitionedbetween water and ethyl acetate. The organic phase was washed withwater, brine, dried over anhydrous sodium sulfate, and concentrated invacuo to give a residue. The residue was purified by silica gel columnchromatography, eluting with a 0-100% gradient of hexane and EtOAc. Thepure product fractions were combined and evaporated to give the titlecompound (3.4 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ ppm 3.84-3.96 (m, 2H),4.39-4.54 (m, 2H), 6.99-7.15 (m, 2H), 9.38-9.53 (m, 1H). ESI-MS m/z[M+H]⁺calc'd for C₇H₈INO₂, 266. found, 266.

STEP C: 2-(2-Formyl-4-iodo-1H-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate

To a cooled (0° C.) solution of1-(2-hydroxyethyl)-4-iodo-1H-pyrrole-2-carbaldehyde (3.4 g, 12.83 mmol)and dichloromethane (25 mL) was added Et₃N (7.15 mL, 51.3 mmol). After 5minutes, 4-methylbenzene-1-sulfonyl chloride (2.81 g, 14.75 mmol) wasadded portion wise over a period of 15 minutes, and the reaction mixturewas allowed to warm to room temperature. Following reaction at roomtemperature overnight, water was added and the resulting layers wereseparated. The aqueous layer was extracted with dichloromethane (50 mL).The organic layers were combined, washed with saturated aqueous NaHCO₃and brine, dried over sodium sulfate, and evaporated to give a brownresidue. The residue was purified with petroleum ether to give the titlecompound as a brown solid, which was used without further purification(3.8 g, 71%). ESI-MS m/z [M+H]⁺calc'd for C₁₄H₁₄INO₄S, 420. found, 420.

STEP D: 2-(2-(Hydroxymethyl)-4-iodo-1H-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate

To a cooled (0° C.) solution of 2-(2-formyl-4-iodo-1H-pyrrol-1-yl)ethyl4-methylbenzenesulfonate (3.5 g, 8.35 mmol) and EtOH (25 mL) was slowlyadded sodium borohydride (0.164 g, 4.34 mmol). After 30 minutes, thereaction mixture was allowed to warm to room temperature and to reactfor an additional hour. The pH of the reaction mixture was adjusted to−6. The solvent was removed using a rotary evaporator and the resultingresidue was partitioned between water and dichloromethane. The organicphase was washed with water, brine, dried over sodium sulfate, andconcentrated. The resulting residue was suspended in a mixture of etherand hexane and then filtered to give the title compound as an off-whitesolid (2.75 g, 78%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.42 (s, 3H),4.05-4.21 (m, 2H), 4.21-4.36 (m, 4H), 5.00 (t, J=5.18 Hz, 1H), 6.00 (d,J=1.77 Hz, 1H), 6.75 (d, J=1.77 Hz, 1H), 7.43 (m, J=8.34 Hz, 2H), 7.64(m, J=8.34 Hz, 2H). ESI-MS m/z [M+H]⁺calc'd for C₁₄H₁₆1 NO₄S, 422.found, 404.

STEP E: 7-Iodo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine

To a stirred mixture of sodium hydride (0.261 g, 6.53 mmol) and THF (10mL) was slowly added a solution of2-(2-(hydroxymethyl)-4-iodo-1H-pyrrol-1-yl)ethyl4-methylbenzenesulfonate (2.75 g, 6.53 mmol) and THF (25 mL). Thereaction mixture was stirred at room temperature for 30 hours, thendiluted with water (20 mL) and extracted with EtOAc (2×60 mL). Theorganic phase was dried over sodium sulfate, evaporated, and purifiedusing silica gel column (80 g) chromatography, eluting with a gradientof 0-100% hexane and EtOAc. The pure compound fractions were combinedand evaporated to give the title compound as a tan solid, which turnedgreen on standing (1.02 g, 63%). ESI-MS m/z [M+H]⁺calc'd for C₇H₈INO,250. found, 250.

STEP F: 7-(Tributylstannyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine

To a cold (−78° C.) mixture of7-iodo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (300 mg, 1.205 mmol)and THF (10 mL) was added n-butyllithium (0.530 mL, 1.325 mmol) dropwiseunder a nitrogen atmosphere. The reaction mixture was stirred at −78° C.for 60 minutes, after which tributylchlorostannane (0.392 mL, 1.445mmol) was added. The reaction mixture was stirred at −78° C. 60 minutes,then warmed to room temperature and stirred for 1 hour. The reaction wasquenched with brine (10 mL) and extracted with EtOAc (2×25 mL). Theorganic phase was separated, dried over sodium sulfate, concentrated,and purified via flash column chromatography to give the title compoundas an oil, which was used without further purification (300 mg, 60%).

PREPARATION 21:1,3-Dimethyl-5-(tributylstannyl)-1H-thieno[2,3-c]pyrazole

STEP A: 1,3-Dimethyl-1H-thieno[2,3-c]pyrazole

A mixture of 1,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (2g, 10.19 mmol), copper (1.943 g, 30.6 mmol) and quinoline (10 mL, 85mmol) were heated to 200° C. for 1 hour in a Biotage Initiatormicrowave. Following heating, the mixture was extracted with ethylacetate (3×100 mL) and 3N HCl (200 mL). The organic layers werecombined, dried over sodium sulfate, concentrated, and purified viasilica gel flash chromatography, eluting with a gradient of 10-40% EtOAcand hexane to give the title compound as a clear oil (1.07 g, 69%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.32 (s, 9H), 3.83 (s, 3H), 6.98 (d, J=5.40Hz, 1H), 7.09 (d, J=4.90 Hz, 1H). ESI-MS m/z [M+H]⁺calc'd for C₇H₈N₂S,153. found, 153.

STEP B: 1,3-Dimethyl-5-(tributylstannyl)-1H-thieno[2,3-c]pyrazole

To a cold (−78° C.) mixture of 1,3-dimethyl-1H-thieno[2,3-c]pyrazole(1.0 g, 6.57 mmol) and THF (50 mL) was added n-butyllithium (4.52 mL,7.23 mmol) dropwise and allowed under a nitrogen atmosphere. Thereaction mixture was stirred at −78° C. for 1 hour. To this solution wasadded tributylchlorostannane (2.13 mL, 7.88 mmol) and the mixture wasstirred at −78° C. for 1 hour and then warmed to room temperature over aperiod of 2 hours. The reaction was quenched with brine (100 mL) andextracted with ethyl acetate (2×100 mL). The organic layers werecombined, dried over sodium sulfate, concentrated, and purified viasilica gel flash chromatography, eluting with 20% EtOAc and hexane togive the title compound as a clear oil (1.60 g, 55%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.86 (t, J=7.33 Hz, 9H), 1.02-1.06 (m, 6H), 1.30 (dq,J=7.29, 14.75 Hz, 6H), 1.44-1.64 (m, 6H), 2.31 (s, 3H), 3.80 (s, 3H),6.94 (s, 1H).

PREPARATION 22: Ethyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolizine-7-carboxylate

STEP A: Ethyl 2-bromoindolizine-7-carboxylate

A mixture of 4-bromo-1H-pyrrole-2-carbaldehyde (1.00 g, 5.75 mmol),(E)-ethyl 4-bromobut-2-enoate (1.555 mL, 11.49 mmol), and potassiumcarbonate (1.74 g, 12.6 mmol) in DMF (20 mL) was stirred overnight atroom temperature under a nitrogen atmosphere. Following reaction, thesolution was extracted with ethyl acetate (2×100 mL) and water (100 mL).The organic layers were combined, dried over sodium sulfate,concentrated, and purified via silica gel flash chromatography, elutingwith a gradient of 10-30% EtOAc and hexane to give, upon removal ofsolvent, the title compound as a purple solid (350 mg, 23%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.32 (t, J=7.40 Hz, 3H), 4.31 (q, J=5.40 Hz, 2H),6.92 (s, 1H), 7.02-7.03 (m, 1H), 7.93 (s, 1H), 8.13 (s, 1H), 8.28-8.29(m, 1H). ESI-MS m/z [M+H]⁺calc'd for C₁₁H₁₀BrNO₂, 268. found, 268.

STEP B: Ethyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolizine-7-carboxylate

A mixture of ethyl 2-bromoindolizine-7-carboxylate (100 mg, 0.373 mmol),bis(pinacolato)diboron (227 mg, 0.895 mmol), PdCl₂(dppf) (13.65 mg,0.019 mmol), and potassium acetate (110 mg, 1.12 mmol) in DMSO (3 mL)was heated to 80° C. in an oil bath overnight. The solution wasextracted with diethyl ether (2×20 mL) and water (30 mL). The organiclayers were combined, dried over magnesium sulfate, and concentrated togive the title compound, which was used without further purification(328 mg). ESI-MS m/z [M+H]⁺calc'd for C₁₂H₂₂BNO₄, 316. found, 316.

PREPARATION 23:6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolizin-1-one

STEP A: 6-Bromo-2,3-dihydro-1H-pyrrolizin-1-one

A mixture of 2,3-dihydro-1H-pyrrolizin-1-one (300 mg, 2.48 mmol) in THF(20 mL) was cooled to −10° C. in a brine bath. N-Bromosuccinimide (441mg, 2.48 mmol) in THF (5 mL) was added dropwise, and the reactionmixture was stirred at −10° C. for 1 hour. The reaction was subsequentlyquenched with water (100 mL) and extracted with ethyl acetate (2×100mL). The organic layers were combined and dried and to give the titlecompound, which was used without further purification (520 mg). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 3.02-3.05 (m, 2H), 4.17-4.20 (m, 2H), 6.58 (d,J=4.40 Hz, 1H), 6.67 (d, J=3.90 Hz, 1H). ESI-MS m/z [M+H]⁺calc'd forC₇H₆BrNO, 200. found, 200.

STEP B:6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolizin-1-one

A mixture of 6-bromo-2,3-dihydro-1H-pyrrolizin-1-one (520 mg, 2.60mmol), bis(pinacolato)diboron (1584 mg, 6.24 mmol), PdCl₂(dppf) (95 mg,0.130 mmol), and potassium acetate (765 mg, 7.80 mmol) in DMSO (12 mL)was heated to 80° C. in an oil bath overnight. The solution wasextracted with ether (2×20 mL) and water (30 mL). The organic layerswere combined, dried over magnesium sulfate, and concentrated to givethe title compound, which was used without further purification (1.56g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 12H), 3.01-3.04 (m, 2H),4.28-4.30 (m, 2H), 7.51 (s, 1H), 7.92 (s, 1H). ESI-MS m/z [M+H]⁺calc'dfor C₁₃H₁₈BNO₃, 248. found, 248.

PREPARATION 24: tert-Butyl (1S,2R)-2-aminocyclohexylcarbamate,(S)-mandelic acid salt

STEP A: A. cis-N-(2-Aminocyclohexyl)-2,2,2-trifluoroacetamide

To a 12-L 4-neck cylindrical jacketed vessel equipped with an overheadstirrer, J-KEM thermocouple, and an addition funnel, was charged asolution of cis-cyclohexane-1,2-diamine (500.0 g, 4.378 mole) in EtOH(2.5 L) under nitrogen. The vessel was cooled to −5° C. Ethyltrifluoroacetate (521 mL, 1.00 eq, Acros lot # A0267844) was charged tothe addition funnel and was added dropwise to the reaction mixture overa period of 1 hour and 45 minutes to afford the title compound in EtOH,which was carried forward into the next step.

STEP B: cis-tert-Butyl 2-(2,2,2-trifluoroacetamido)cyclohexylcarbamate

A solution of di-tert-butyl dicarbonate (1.00 kg, 4.597 mole, 1.05 eq,Oakwood lot # DO8E) in EtOH (500 mL) was prepared and added dropwiseover a period of 35 minutes to the solution ofcis-N-(2-aminocyclohexyl)-2,2,2-trifluoroacetamide in EtOH from Step A.During the addition, the reaction temperature was maintained at <15° C.Once the addition was complete, the solution, which turned to a slurryafter 1 hour, was stirred for 4 hours to afford the title compound inEtOH, which was carried forward into the next step.

STEP C: cis-tert-Butyl 2-aminocyclohexylcarbamate

To the mixture of cis-tert-butyl2-(2,2,2-trifluoroacetamido)cyclohexylcarbamate in EtOH from Step B, wasadded a solution of NaOH (500.0 g of a 50 wt % solution in water, 1.42eq) in water (1.0 L) portion wise over a period of 15 minutes, whilemaintaining a reaction temperature <15° C. Once the addition wascomplete, the reaction temperature was allowed to rise to roomtemperature, and the reaction mixture was stirred at RT overnight (16hours). The batch (6 L) was distilled under reduced pressure (˜200 mBar)to a volume of −3.4 L. Water (2.0 L) was added and the distillation wascontinued (at −200 mBar) until the volume of the mixture was about 4.0 Land the solution had turned milky in appearance. The batch was cooled to25° C., diluted with IPAc (3.5 L) and stirred for 10 minutes. Followingphase separation, the aqueous phase was extracted with IPAc (1.5 L) andthe phases separated. The combined organic extracts were washed withwater (1.5 L) and then with an aqueous solution of NaCl (5 wt %, 1.5 L).The organic phase (5.8 L) was distilled under reduced pressure (˜200mBar) until the volume of the mixture was ˜2.0 L. This afforded thetitle compound as a crude racemic product in IPAc, which was carriedforward into the next step. Proton NMR analysis showed the presence ofEtOH (2.3 mole %) and KF analysis indicated the presence of water(0.58%).

STEP D: tert-Butyl (1S,2R)-2-aminocyclohexylcarbamate, (S)-mandelic acidsalt

The mixture of cis-tert-butyl 2-aminocyclohexylcarbamate in IPAc fromStep C was heated to 80° C. and then a solution of (S)-mandelic acid(333.0 g, 2.189 mole, 0.5 eq) in IPAc (8.0 L) was added over a period of45 minutes while maintaining the reaction temperature above 70° C.Crystallization began during the addition of the last 0.5 L of mandelicacid solution (no seed was added). Once the addition was complete, thebatch was heated to 82° C. and was stirred for 13 hours under nitrogen,resulting in a beige slurry having a dark orange supernatant (visibleupon sitting). The batch was cooled to 25° C. and was filtered through a26 cm diameter Buchner funnel under vacuum over a period of less than 2minutes. The filter cake was conditioned for 5 minutes and then washedwith IPAc (1.5 L), which had been used to rinse the reaction vessel.After additional conditioning for 5 minutes, the filter cake was againwashed with an IPAc rinse (1.5 L). The filter cake was conditioned for30 minutes and then tray dried in a vacuum oven at 40-50° C. for 5 hoursto give the title compound (550 g, 34% over 4 steps, 99.1% ee via chiralHPLC analysis following derivatization with 4-methoxy benzoyl chlorideand work-up).

PREPARATION 25: tert-Butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

STEP A: tert-Butyl (1S,2R)-2-aminocyclohexylcarbamate (free base)

To a 10-L carboy equipped with a magnetic stirrer was charged tert-butyl(1S,2R)-2-aminocyclohexylcarbamate, (S)-mandelic acid salt (570.56 g,1.5580 mol, 1.25 eq). Water (2.8 L) and MTBE (2.28 L) were added andagitation was begun. To the resulting white slurry was added 2N NaOHsolution (1.25 L). The mixture was stirred at room temperature for 30minutes. The phases were separated in a 22-L separatory funnel. Theaqueous layer was extracted with MTBE (2.28 L), and the organic extractswere combined, washed with water (2 L) and brine (2 L), and transferredto a 5-L 4-neck RBF equipped with reduced-pressure distillationapparatus. The mixture was concentrated under reduced pressure (240-245torr) to a volume of about 2 L over a period of about 5 hours. Themixture was stored at room temperature overnight. Isopropanol (2 L) wasadded to the mixture, which was distilled under a vacuum of 230-234 torrfor 75 minutes and then under a vacuum of 123-125 torr for 2 hours and40 minutes, resulting in a volume of about 2 L. A second portion of IPA(2 L) was added and the mixture was stored at room temperatureovernight. The mixture was subsequently distilled at a pressure of112-115 torr for 5 hours. Isopropanol (800 mL) was added and the mixturewas distilled under a vacuum of 114-116 torr for 3 hours. The residualwas stored at room temperature overnight, whereupon distillation wascontinued under a vacuum of 114-116 torr for 4 hours until about 2 L ofthe material remained. NMR analysis of the residual indicated that MTBEwas not detectable.

STEP B: tert-Butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To the 5-L RBF containing tert-butyl (1S,2R)-2-aminocyclohexylcarbamate(STEP A) was added tert-butyl4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(400.0 g, 1.246 mol, 1 eq). To this mixture was added IPA (400 mL), DMSO(400 mL) and DIPEA (282 mL, 1.3 eq). The resulting pink slurry washeated up to 78° C. and was stirred for 34 hours. The mixture was thencooled to room temperature and was stirred over the weekend. HPLCanalysis indicated the presence of 1.6% of the starting material, 4.63%of the des-Boc side product, 72.38% of the desired product, and 11.23%of an isomer. ¹H NMR analysis indicated a ratio of 5.49 of the IPA/DMSO.Isopropanol (200 mL) was added to the mixture to adjust the ratio to 6.The slurry was heated up to 78° C. Water (1.6 L) was added over a periodof 1 hour at a rate which kept the temperature of the mixture above 64°C. The mixture was then cooled to room temperature and was stirredovernight. The slurry was filtered the next morning through a frittedglass funnel. The filter cake was washed with IPA/water/DMSO (800 mL,6:4:1) and IPA/water (2×800 mL, 3:2) to give the title compound, whichwas dried under high vacuum at 40-45° C. until a constant weight wasobtained (299.27 g, 48% yield with a 96.6% purity). ¹H NMR (300 MHz,CDCl₃) δ ppm 1.80-1.30 (m, 26H), 4.04 (m, 1H), 4.21 (m, 1H), 4.64 (d,J=0.9 Hz, 1H), 4.85 (br, 1H), 6.08 (br, 1H).

PREPARATION 26: tert-Butyl4-chloro-6,7-difluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

STEP A: 2-Chloro-5,6-difluoronicotinonitrile

To 2,6-dichloro-5-fluoronicotinonitrile (50 g, 262 mmol) was addedspray-dried potassium fluoride (30 g, 516 mmol) followed immediately bythe addition of anhydrous DMSO (125 mL). The reaction mixture wasstirred at 20° C. for 16-20 hours. The progress of the reaction wasclosely monitored by HPLC. When the product concentration reachedmaximum (˜79%), the reaction was worked up immediately. Ethyl acetate(1000 mL) was added to the reaction mixture followed by the addition ofice (50 g). Water (500 mL) was then slowly added with cooling to ensurethe temperature did not exceed 25° C. The organic phase and the aqueousphase were separated. The organic phase was washed with water (400 mL).Active carbon (12 g, Darco G-60, 100 mesh) was added and the mixture wasstirred for 2 hours. The mixture was filtered through a pad of Celite.The filtrate was washed with water (400 mL) and concentrated by rotaryevaporation to a volume of about 120 mL. The concentrate was dilutedwith heptane (150 mL) and the resulting solution was concentrated to avolume of about 150 mL, which resulted in precipitation of solidproduct. The mixture was stirred for 30 minutes at room temperature andfiltered. The filter cake was washed with heptane (100 mL) and dried toafford the title compound (29.5 g, 65%). ¹H NMR (500 MHz, CDCl₃) δ ppm7.92-7.96 (m, 1H).

STEP B: 2-Chloro-5,6-difluoronicotinamide

To a mixture of 2-chloro-5,6-difluoronicotinonitrile (89.66 g, 514mmol), acetamide (66.8 g, 1130 mmol), THF (337.5 mL), and water (113 mL)was added palladium(II) chloride (1.822 g, 10.27 mmol) with stirring.The reaction mixture was stirred at 60° C. for 18 hours under a nitrogenatmosphere. The reaction mixture was subsequently cooled to roomtemperature and was added to a stirred mixture of EtOAc (900 mL), hexane(90 mL) and water (180 mL). The layers were allowed to separate and theaqueous layer was removed. The organic layer was washed with water (180mL) and concentrated on a rotary evaporator at 29° C. to afford an oilthat solidified. The solid was suspended in hexanes (270 mL) andfiltered after 1 hour. The flask was rinsed forward with hexanes (50mL). The filter cake was washed with additional hexanes (20 mL) anddried in a vacuum oven at 40° C. to give the title compound as a lighttan solid (82.21 g, 83%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.93 (s br,1H), 8.10 (s br, 1H), 8.32-8.37 (m 1H).

STEP C:4-Chloro-6,7-difluoro-1-hydroxy-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To an inert 250 mL 3-neck round bottom flask with magnetic stirring wasadded LiHMDS (1M in THF, 57.3 mL, 57.3 mmol). The solution was cooled inan ice/brine bath to achieve an internal temperature of −4° C. To thecooled LiHMDS solution was added dropwise a solution of2-chloro-5,6-difluoronicotinamide (4.41 g, 22.9 mmol) dissolved in2-methyltetrahydrofuran (22 mL) and N,N-dimethylformamide (8.87 mL, 115mmol) while maintaining the internal temperature between +1° C. to −3°C. The reaction mixture was stirred for 30 minutes at a temperature ofabout 0° C. The reaction was quenched by adding it dropwise to a cooled(0-5° C.) stirred mixture of 2M aqueous HCl (74.4 mL, 149 mmol) and IPAc(75 mL) while maintaining an internal temperature <10° C. Once thetransfer was completed, the biphasic solution was transferred to aseparatory funnel and the lower aqueous layer was removed and extractedwith IPAc (75 mL). The organic layers were combined, washed with water(25 mL), dried over sodium sulfate, and concentrated on a rotaryevaporator. The resulting solid was suspended in heptane (20 mL), andthe mixture was stirred for 90 minutes and filtered. The filter cake waswashed with heptane (20 mL) and dried to give the title compound as anoff-white solid (4.442 g, 88%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm6.11-6.14 (m, 1H), 6.98 (d, J=8 Hz, 1H), 9.5 (s br, 1H).

STEP D: 4-Chloro-6,7-difluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To an inert 50 mL round bottom flask with magnetic stirring was added4-chloro-6,7-difluoro-1-hydroxy-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (4.39g, 19.90 mmol) and trifluoroacetic acid (18.40 mL, 239 mmol). The solidswere suspended with stirring and triethylsilane (7.95 mL, 49.8 mmol) wasadded. The reaction mixture was heated to 60° C. and stirred for 30minutes at that temperature. The reaction mixture was subsequentlycooled to room temperature and added dropwise to MTBE (88 mL) to producea white precipitate. The suspension was cooled to 5° C. for 45 minutes.The solids were filtered, washed with MTBE (20 mL) and air dried on thefilter to afford the title compound (3.336 g, 82%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.58 (s, 2H), 9.13 (s br, 1H).

STEP E: tert-Butyl4-chloro-6,7-difluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a 50 mL 3-neck round bottom flask with magnetic stirring was added4-chloro-6,7-difluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (3.25 g, 15.89mmol) and DCM (23 mL). The suspension was cooled to 5° C. and Et₃N (4.43mL, 31.8 mmol) was added followed by DMAP (0.019 g, 0.159 mmol). Asolution of di-tert-butyl dicarbonate (4.16 g, 19.07 mmol) in DCM (6.5mL) was added dropwise over a period of 2 minutes during which thereaction mixture turned dark red. The reaction mixture was stirred andallowed to warm slowly to 14° C. over a 4 hour period after which HPLCanalysis showed 11% starting material remained. Additional DMAP (0.019g, 0.159 mmol) was added to provide complete consumption of the startingmaterial within 1 hour. The reaction suspension was then added to IPA(65 mL). The red suspension was cooled to 5° C. for 5 minutes before thesolids were filtered, washed with IPA (10 mL), and dried in a vacuumoven at 45° C. overnight to yield the title compound as a reddish solid(3.87 g, 80%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53 (s, 9H), 4.94 (s,2H).

PREPARATION 27: tert-Butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-e]pyridine-2(3H)-carboxylate

To a mixture of tert-butyl4-chloro-6,7-difluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(42.5 g, 139 mmol) and tert-butyl(3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (36.2 g, 167 mmol) wasadded IPA (425 mL) followed by 4-methylmorpholine (18.40 mL, 167 mmol).The reaction mixture was stirred at 60° C. for 20 hours under a nitrogenatmosphere. HPLC analysis indicated that the reaction was complete. Thereaction mixture was subsequently cooled to room temperature and water(890 mL) was added slowly. The suspension was cooled in an ice/waterbath to 6° C. and was stirred for 1 hour. The solids were collected byfiltration and washed with water (30 mL) used to rinse the reactionvessel. The filter cake was washed with additional water (350 mL) andallowed to dry on the filter. The filter cake was subsequently dried ina vacuum oven at 60° C. over the weekend to afford the title compound(64.78 g, 93%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36 (s, 9H), 1.50 (s,9H), 1.59-1.61 (m, 1H), 1.97-1.99 (m, 1H), 1.97-1.99 (m, 1H), 3.46-3.49(m, 2H), 3.80-3.83 (m, 3H), 4.31-4.33 (m, 1H), 4.73 (s, 1H), 6.59 (d,J=7.30 Hz, 1H), 7.43 (d, J=7.30 Hz, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂₂H₃₀ClFN₄O₆, 501. found, 501.

PREPARATION 28: tert-Butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-7-fluoro-4-(3-methylisothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-e]pyridine-2(3H)-carboxylate

METHOD A: A solution of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(100 mg, 0.200 mmol), 3-methyl-5-(tributylstannyl)isothiazole (117 mg,0.301 mmol) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.100mmol) in toluene (10 mL) was heated to 120° C. for 45 minutes viamicrowave irradiation. The reaction mixture was poured into water andwas extracted with EtOAc. The extracts were dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by silica gelchromatography (Flash 60 column) eluting with hexane/EtOAc (4:1) to givethe title compound as a yellow solid (84.4 mg, 75%). ¹H NMR (500 MHz,CDCl₃) δ ppm 1.29-1.51 (m, 11H), 1.53-1.70 (m, 11H), 1.71-1.88 (m, 3H),2.03-2.17 (m, 1H), 2.58 (s, 3H), 4.07-4.21 (m, 2H), 4.72 (s, 2H), 4.89(br s, 1H), 6.36 (br s, 1H), 8.74 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂₇H₃₆FN₅O₅S, 562. found, 562.

METHOD B: To a solution of3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole(24.39 g, 108 mmol) in DMA (110 mL) was added cesium fluoride (10.76 g,70.1 mmol). During the CsF addition the temperature of the reactionmixture rose to 26° C. The reaction mixture was cooled to 22° C. and wasstirred for 90 minutes. The reaction mixture was degassed bysuccessively evacuating and purging the reaction vessel with nitrogen(3×). A portion of the degassed boronate solution (25 mL) was then addedto a mixture of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(21.20 g, 42.5 mmol) and Pd-118 (Johnson-Matthey, 1.448 g, 2.124 mmol)which was suspended in DMA (100 mL) and degassed by nitrogen purging(3×). The reaction mixture was heated to 80° C. over a period of 15minutes. Once the temperature of the reaction mixture reached about 65°C., the remainder of the boronate solution was added slowly over aperiod of 60 minutes. The reaction mixture was then heated at 77° C. for14 hours and was subsequently cooled to room temperature. The reactionmixture was extracted with EtOAc (2×500 mL) and water (500 mL). Theorganic extracts were combined, dried over sodium sulfate, concentrated,and purified via silica gel flash chromatography, eluting with agradient of 5-20% EtOAc and hexanes/dichloromethane (1:1). The resultingbrown solid was triturated with EtOAc/hexanes (1:9, 200 mL) and wascollected via vacuum filtration to give a crude tan solid (ca 19 g). Thecrude product was dispersed in absolute ethanol (200 mL). The mixturewas heated to 60° C. for 1 hour and was allowed to cool to roomtemperature. The mixture was further cooled to 0° C. in an ice bath. Theprecipitate was collected and dried to afford the title compound as atan solid (13.86 g, 58%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.08 (m,2H), 1.34 (s, 9H), 1.34-1.36 (m, 2H), 1.53 (s, 9H), 1.55-1.57 (m, 2H),1.61-1.63 (m, 2H), 2.49 (s, 3H), 3.93-3.94 (m, 1H), 4.10-4.11 (m, 1H),4.79 (s, 2H), 6.70-6.71 (br s, 1H), 7.16-7.17 (br s, 1H), 8.52 (s, 1H).ESI-MS m/z [M+H]⁺calc'd for C₂₇H₃₆FN₅O₅S, 562. found, 562.

PREPARATION 29:4,6-Dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one

To a solution of diisopropylamine (96 g, 0.94 mol) in THF (800 mL) wasslowly added n-butyllithium (379 mL, 0.95 mol, 2.5 M) at −78° C. Themixture was stirred at the same temperature for 30 minutes. To themixture was added 2,6-dichloro-5-fluoronicotinic acid (90 g, 0.43 mol)in THF (500 mL). The solution was stirred for an additional 2 h. To themixture was added DMF (154 mL, 1.94 mol) dropwise, The mixture wasstirred for 1 h, after which 2N HCl (1.54 L) (pH<1) was introduced. Themixture was subsequently extracted with EtOAc and the organic layerswere basified with aqueous NaHCO₃ (pH >8). The aqueous layer wasseparated, acidified with 2N HCl (1.2 L) (pH<1), and extracted withEtOAc. The organic layer was washed with water and brine, dried overanhydrous Na₂SO₄, and filtered. The filtrate was concentrated underreduced pressure and the resulting residue was washed with DCM to givethe title compound as a reddish solid (81.6 g, 80%). ¹H NMR (DMSO-d₆,400 MHz) δ ppm 6.85 (s, 1H), 8.83 (s, 1H). [M+H] calc'd for C₇H₂C₁₂FNO₃,238. found, 238.

PREPARATION 30:(E)-2,6-Dichloro-4-(((2,4-dimethoxybenzyl)imino)methyl)-5-fluoronicotinicacid

To a solution of (2,4-dimethoxyphenyl)methanamine (40.5 g, 242.0 mmol)in MeOH (250 mL) was added4,6-dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one (55.0 g,231.0 mmol). The mixture was stirred for 0.5 h, filtered, and washedwith petroleum ether to give the title compound as a white solid (73.0g, 82%). ¹H NMR (CDCl₃, 400 MHz) δ ppm 3.75 (s, 3H), 3.79 (s, 3H), 3.93(s, 2H), 6.30 (s, 1H), 6.40-6.42 (m, 2H), 7.12 (d, J=8.4 Hz, 1H). [M+H]calc'd for C₁₆H₁₃C₁₂FN₂O₄, 387. found, 387.

PREPARATION 31:4,6-Dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a mixture of(E)-2,6-dichloro-4#(2,4-dimethoxybenzyl)imino)methyl)-5-fluoronicotinicacid (72.0 g, 186.5 mmol) in THF (700 mL) was added methyllithium (933.0mL, 933.0 mmol) dropwise at −78° C. After the addition was complete, thesolution was stirred for an additional 2 h. The reaction mixture wasthen acidified with 1N HCl to pH 6, heated to 50° C. for 7 h, andsubsequently extracted with EtOAc. The organic layer was washed withbrine and dried over anhydrous Na₂SO₄. The concentrated crude waspurified by silica gel chromatography to give the title compound as awhite solid (14 g, 15%). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.58 (d, J=6.8Hz, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 4.35 (d, J=14.4 Hz, 1H), 4.52 (q,J=6.8 Hz, 1H), 5.07 (d, J=14.4 Hz, 1H), 6.43-6.45 (m, 2H), 7.28 (d,J=9.2 Hz, 1H). [M+H] calc'd for C₁₂H₁₅C₁₂FN₂O₃, 385. found, 385.

PREPARATION 32:4,6-Dichloro-7-fluoro-1-methyl-1H-pyrrolo[3,4-c]pyridin-1N 3(2H)-one

4,6-Dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one(14.0 g, 36.4 mmol) was dissolved in TFA (70 mL) and triethylsilane (5.1g, 43.7 mmol). The mixture was heated to reflux and additionaltriethylsilane (1.3 g, 10.9 mmol) was added until the red-coloredsolution became clear. TFA and triethylsilane were removed under reducedpressure. The mixture was basified with aq. NaHCO₃ to pH 7 and filteredto give the title compound (7.3 g, 85%). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm1.42 (d, J=6.8 Hz, 3H), 4.92 (q, J=6.8 Hz, 2H), 9.25 (s, 1H). [M+H]calc'd for C₈H₅C₁₂FN₂O, 235. found, 235.

PREPARATION 33: tert-Butyl4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a mixture of4,6-dichloro-7-fluoro-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (7.3g, 31.1 mol) in acetonitrile (50 mL) was added di-tert-butyl dicarbonate(7.5 g, 34.2 mol) dropwise while stirring the mixture in an ice bath.After the addition was complete, the mixture was stirred for anadditional 0.5 h. The resulting solid was collected by filtration andwashed with acetonitrile and ethyl acetate to give a white solid (5.5 g,53%). ¹H NMR (DMSO-d₆) δ ppm 1.53 (s, 9H), 1.61 (d, J=6.8 Hz, 3H), 5.30(q, J=6.8 Hz, 2H). [M+H] calc'd for C₁₂H₁₁C₁₂FN₂O₃, 321. found, 321.

PREPARATION 34: tert-Butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-chloro-7-fluoro-1-methyl-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a flask containing a mixture of tert-butyl4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(1 g, 2.98 mmol) in 2-propanol (7 mL) was added tert-butyl((1S,2R)-2-aminocyclohexyl)carbamate (767 mg, 3.58 mmol) dissolved inDMSO (1.2 mL) followed by DIPEA (0.677 mL, 3.88 mmol). The flask wasequipped with a condenser and nitrogen blanket and was lowered into a90° C. oil bath, where the reaction mixture was allowed to stir for 16h. The mixture was subsequently purified via preparative HPLC to givethe title compound as a white solid (490 mg, 32%). [M+H] calc'd forC₁₉H₂₆ClFN₄O₃, 413. found, 413.

PREPARATION 35: tert-Butyl((3R,4R)-4-((4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)tetrahydro-2H-pyran-3-yl)carbamate

To a sealed tube was added4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one(430 mg, 1.12 mol), tert-butyl((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate (7.5 g, 34.2 mol),and DIPEA (0.97 mL, 5.58 mmol). The mixture was heated in the sealedtube at 95° C. for 72 h. The mixture was purified via preparative HPLCto give the title compound as a yellow solid (100 mg, 16%). [M+H] calc'dfor C₂₇H₃₄ClFN₄O₆, 565. found, 565.

Example 16-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-(difluoromethyl)isothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

STEP A: tert-Butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(3-(difluoromethyl)isothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

A solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(50 mg, 0.100 mmol), 3-(difluoromethyl)-5-(tributylstannyl)isothiazole(296 mg, 0.699 mmol) and tetrakis (triphenylphosphine)palladium(0) (57.7mg, 0.050 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutesvia microwave irradiation. The reaction mixture was poured into waterand was extracted with EtOAc. The extracts were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) toyield the title compound as a mixture with byproduct. The crude productwas used without further purification.

STEP B:6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-(difluoromethyl)isothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a stirred solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(3-(difluoromethyl)isothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(59.8 mg, 0.100 mmol) in EtOAc (2.0 mL) and MeOH (10 mL) was added 4NHO/dioxane (10.0 mL, 40.0 mmol). The reaction mixture was heated to 60°C. for 1 h and then concentrated in vacuo. The resulting crude materialwas reconstituted in DMF and purified via preparative mass triggeredLCMS, eluting with a gradient of 15-40% ACN (0.035% TFA) in H₂O (0.05%TFA). The collected fractions were combined and the solvent was removedvia rotary evaporation to yield the title compound as a TFA salt (0.5mg, 1%). ¹H NMR (500 MHz, CD₃OD) δ ppm 1.89-1.96 (m, 1H), 2.08-2.22 (m,1H), 3.68-3.78 (m, 1H), 3.87-3.96 (m, 1H), 4.03-4.17 (m, 3H), 4.40-4.59(m, 3H), 6.65-6.95 (m, 1H), 9.15 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₁₆H₁₆F₃N₅O₂S, 400. found, 400.

Example 26-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

STEP A: tert-Butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-4-(3-vinylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

A solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(75 mg, 0.150 mmol), 5-(tributylstannyl)-3-vinylisothiazole (90 mg,0.225 mmol) and tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.075mmol) in toluene (4.0 mL) was heated to 120° C. for 45 minutes viamicrowave irradiation. The reaction mixture was poured into water andwas extracted with EtOAc. The extracts were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gelchromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to givethe title compound as a yellow solid (59.2 mg, 69%). ESI-MS m/z[M+H]⁺calc'd for C₂₇H₃₄FN₅O₆S, 576. found, 576.

STEP B: tert-Butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a stirred solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-4-(3-vinylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(58 mg, 0.101 mmol) in MeOH (1.0 mL) was added Pd/C (30 mg, 0.282 mmol)under N₂ atmosphere. The mixture was stirred at room temperatureovernight under H₂ atmosphere. The solids were removed by filtration,and the filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography (Flash 60 column) eluting with hexane/EtOAc(1:1) to give the title compound as a yellow solid (54.9 mg, 94%). ¹HNMR (500 MHz, CDCl₃) δ ppm 1.36 (t, J=7.57 Hz, 3H), 1.48 (br s, 9H),1.61 (s, 9H), 1.71-1.82 (m, 1H), 2.20-2.33 (m, 1H), 2.91 (q, J=7.60 Hz,2H), 3.64 (t, J=11.72 Hz, 1H), 3.74 (d, J=11.72 Hz, 1H), 3.91-3.99 (m,1H), 4.01-4.10 (m, 2H), 4.23-4.34 (m, 1H), 4.72 (s, 2H), 5.37 (d, J=6.83Hz, 1H), 6.47 (br s, 1H), 8.78 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂₇H₃₆FN₅O₆S, 578. found, 578.

STEP C:6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a stirred solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(53 mg, 0.092 mmol) in MeOH (10 mL) was added 4N HCl/dioxane (10.0 mL,40.0 mmol). The mixture was heated to 60° C. for 1 hour and thenconcentrated in vacuo. The residue was triturated with EtOAc andfiltered. The filter cake was washed with EtOAc to give a yellow solid,which was suspended into EtOH. The mixture was stirred at 80° C. for 30minutes and then cooled to room temperature. The resulting precipitatewas collected by filtration and washed with EtOH to give a hydrochloridesalt of the title compound as an off-white solid (26.8 mg, 70%). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.26 (t, J=7.57 Hz, 3H), 1.74-1.83 (m, 1H),2.07-2.20 (m, 1H), 2.81 (q, J=7.60 Hz, 2H), 3.57-3.67 (m, 1H), 3.73-3.84(m, 2H), 3.96-4.09 (m, 2H), 4.28-4.36 (m, 1H), 4.43-4.53 (m, 2H), 7.46(d, J=5.37 Hz, 1H), 8.05 (br s, 3H), 8.68 (s, 1H), 8.80 (s, 1H). ESI-MSm/z [M+H]⁺calc'd for C₁₂H₂₀FN₅O₂S, 378. found, 378.

Example 36-((1R,2S)-2-Aminocyclohexylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

STEP A: tert-Butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-7-fluoro-3-oxo-4-(3-vinylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

A solution of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(80 mg, 0.160 mmol), 5-(tributylstannyl)-3-vinylisothiazole (96 mg,0.240 mmol), and tetrakis(triphenylphos-phine)palladium(0) (93 mg, 0.080mmol) in toluene (4.0 mL) was heated to 120° C. for 45 minutes viamicrowave irradiation. The reaction mixture was subsequently poured intowater and was extracted with EtOAc. The extracts were dried over Na₂SO₄and were concentrated in vacuo. The residue was purified by silica gelchromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to givethe title compound as a yellow solid, which was used without furtherpurification (81.3 mg, 88%). ESI-MS m/z [M+H]⁺calc'd for C₂₈H₃₆FN₅O₅S,574. found, 574.

STEP B: tert-Butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-7-fluoro-3-oxo-4-(3-vinylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a stirred solution of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-7-fluoro-3-oxo-4-(3-vinylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(80 mg, 0.139 mmol) in MeOH (1.0 mL) was added Pd/C (30 mg, 0.282 mmol)under N₂ atmosphere. The mixture was stirred at room temperatureovernight under H₂ atmosphere. The solids were removed by filtration,and the filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography (Flash 60 column) eluting with hexane/EtOAc(1:1) to yield the title compound as a yellow solid. ESI-MS m/z[M+H]⁺calc'd for C₂₈H₃₈FN₅O₅S, 576. found, 576.

STEP C:6-((1R,2S)-2-Aminocyclohexylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a stirred solution of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(80 mg, 0.139 mmol) in MeOH (1.0 mL) was added 4N HCl/dioxane (1.0 mL,4.00 mmol). The mixture was heated to 60° C. for 1 h and wassubsequently concentrated in vacuo. The residue was triturated withEtOAc and filtered. The filter cake was washed with EtOAc to give ayellow solid, which was suspended into EtOH. The mixture was stirred at80° C. for 30 minutes and then cooled to room temperature. The resultingprecipitate was collected by filtration and washed with EtOH to give ahydrochloride salt of the title compound as an off-white solid (20.6 mg,36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.26 (t, J=7.57 Hz, 3H), 1.39-1.55(m, 2H), 1.56-1.83 (m, 4H), 1.83-2.04 (m, 2H), 2.81 (q, J=7.65 Hz, 2H),3.77 (br s, 1H), 4.18-4.30 (m, 1H), 4.41-4.53 (m, 2H), 7.16 (d, J=5.86Hz, 1H), 7.82 (br s, 3H), 8.66 (s, 1H), 8.80 (s, 1H). ESI-MS m/z[M+H]⁺calc'd for C₁₈H₂₂FN₅OS, 376. found, 376.

Example 46-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(isothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

STEP A: tert-Butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(isothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

A solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(60 mg, 0.120 mmol), 5-(tributylstannyl)isothiazole (67.2 mg, 0.180mmol) and tetrakis(triphenylphosphine)palladium(0) (69.2 mg, 0.060 mmol)in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwaveirradiation. The reaction mixture was subsequently poured into water andwas extracted with EtOAc. The extracts were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gelchromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to givethe title compound as a yellow solid. ESI-MS m/z [M+H]⁺calc'd forC₂₅H₃₂FN₅O₆S, 550. found, 550.

STEP B:6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(isothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a stirred solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(isothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(65.8 mg, 0.120 mmol) in MeOH (1.0 mL) was added 4N HCl/dioxane (1.0 mL,4.00 mmol). The reaction mixture was heated to 60° C. for 1 hour and wassubsequently concentrated in vacuo. The residue was triturated withEtOAc and filtered. The filter cake was washed with EtOAc to give ayellow solid, which was suspended into EtOH. The mixture was stirred at80° C. for 30 minutes and allowed to cool to room temperature. Theresulting precipitate was collected by filtration and washed with EtOHto give a hydrochloride salt of the title compound as an off-white solid(26.5 mg, 57%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.74-1.85 (m, 1H),2.08-2.23 (m, 1H), 3.56-3.68 (m, 1H), 3.80 (d, J=11.23 Hz, 2H),3.96-4.11 (m, 2H), 4.29-4.39 (m, 1H), 4.42-4.55 (m, 2H), 7.49 (d, J=5.37Hz, 1H), 8.08 (br s, 3H), 8.63 (s, 1H), 8.71 (s, 1H), 8.96 (s, 1H).ESI-MS m/z [M+H]⁺calc'd for C₁₅H₁₆FN₅O₂S, 350. found, 350.

Example 56-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(isothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

STEP A: tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-7-fluoro-4-(isothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

A solution of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(60 mg, 0.120 mmol), 5-(tributylstannyl)isothiazole (67.5 mg, 0.180mmol) and tetrakis(triphenylphosphine)palladium(0) (69.5 mg, 0.060 mmol)in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwaveirradiation. The reaction mixture was subsequently poured into water andwas extracted with EtOAc. The extracts were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gelchromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to givethe title compound as a yellow solid. ESI-MS m/z [M+H]⁺calc'd forC₂₆H₃₄FN₅O₅S, 548. found, 548.

STEP B:6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(isothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a stirred solution of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-7-fluoro-4-(isothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(65.9 mg, 0.120 mmol) in MeOH (1.0 mL) was added 4N HCl/dioxane (1.0 mL,4.00 mmol). The reaction mixture was heated to 60° C. for 1 hour and wassubsequently concentrated in vacuo. The residue was triturated withEtOAc and filtered. The filter cake was washed with EtOAc to give ayellow solid, which was suspended into EtOH. The mixture was stirred at80° C. for 30 minutes and allowed to cool to room temperature. Theresulting precipitate was collected by filtration and washed with EtOHto yield a hydrochloride salt of the title compound as an off-whitesolid (18.6 mg, 40%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36-1.55 (m, 2H),1.58-2.06 (m, 6H), 3.77 (br s, 1H), 4.17-4.33 (m, 1H), 4.39-4.54 (m,2H), 7.19 (d, J=5.86 Hz, 1H), 7.88 (br s, 3H), 8.62 (d, J=1.95 Hz, 1H),8.69 (s, 1H), 8.97 (d, J=1.95 Hz, 1H). ESI-MS m/z [M+H]⁺calc'd forC₁₆H₁₈FN₅OS, 348. found, 348.

Example 66-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-cyclopropylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

STEP A: tert-Butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(3-cyclopropylisothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

A solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(50 mg, 0.100 mmol), 3-cyclopropyl-5-(tributylstannyl)isothiazole (62.0mg, 0.150 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.6 mg,0.030 mmol) in toluene (10 mL) was heated to 120° C. for 45 minutes viamicrowave irradiation. The reaction mixture was poured into water andwas extracted with EtOAc. The extracts were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gelchromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to givethe title compound as a yellow solid, which was used without furtherpurification (58.9 mg, 100%). ESI-MS m/z [M+H]⁺calc'd for C₂₈H₃₆FN₅O₆S,590. found, 590.

STEP B:6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-cyclopropylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a stirred solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(3-cyclopropylisothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(58.9 mg, 0.100 mmol) in MeOH (2.0 mL) was added 4N HCl/dioxane (2.0 mL,8.00 mmol). The reaction mixture was heated to 60° C. for 1 hour andthen concentrated in vacuo. The residue was triturated with EtOAc andfiltered. The filter cake was washed with EtOAc to give a yellow solid,which was suspended into EtOH. The mixture was stirred at 80° C. for 30minutes and then cooled to room temperature. The resulting precipitatewas collected by filtration and washed with EtOH to give a hydrochloridesalt of the title compound as an off-white solid (26.5 mg, 62%). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.82-0.92 (m, 2H), 0.95-1.06 (m, 2H), 1.70-1.85(m, 1H), 2.07-2.17 (m, 1H), 2.18-2.26 (m, 1H), 3.56-3.66 (m, 1H),3.72-3.84 (m, 2H), 3.95-4.08 (m, 2H), 4.26-4.36 (m, 1H), 4.41-4.53 (m,2H), 7.46 (d, J=4.88 Hz, 1H), 8.02 (br s, 3H), 8.68 (s, 1H), 8.72 (s,1H). ESI-MS m/z [M+H]⁺calc'd for C₁₈H₂₀FN₅O₂S, 390. found, 390.

Example 76-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(33 mg, 0.066 mmol), 5-fluorobenzo[b]thiophen-2-ylboronic acid (12.91mg, 0.066 mmol) and tetrakis(triphenylphosphine)palladium(0) (76 mg,0.066 mmol) in toluene (3 mL) was heated to 120° C. via microwaveirradiation for 30 minutes. The reaction mixture was diluted with EtOAc(50 mL) and saturated aqueous NaHCO₃ (100 mL). The organic layer wasseparated and the aqueous layer was washed with EtOAc (50 mL). Theorganic layers were combined and dried over Na₂SO₄, and the solvent wasremoved in vacuo to give the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dispersed in TFA and DCM (1:1, 10 mL). The mixturewas stirred at room temperature for 60 minutes and then concentrated.The resulting crude material was reconstituted in MeOH and DCM (6.0 mL)and purified via preparative HPLC, eluting with a gradient of 25-30% ACN(0.035% TFA) and H₂O (0.05% TFA). The collected fractions were combinedand the solvent was stripped to dryness via rotary evaporation to yielda TFA salt of the title compound (12 mg, 44%). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.82 (d, J=9.76 Hz, 1H), 2.15 (d, J=8.30 Hz, 1H), 3.59-3.70 (m,1H), 3.82 (s, 1H), 3.91 (br s, 1H), 3.98-4.11 (m, 2H), 4.38 (br s, 1H),4.43-4.55 (m, 2H), 7.23-7.33 (m, 1H), 7.42 (d, J=4.88 Hz, 1H), 7.76 (dd,J=9.76, 2.44 Hz, 1H), 7.93-8.03 (m, 3H), 8.62-8.74 (m, 1H), 9.41 (s,1H). ESI-MS m/z [M+H]⁺calc'd for C₂₀H₁₈F₂N₄O₂S, 417. found, 417.

Example 85-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiophene-2-carbonitrile

A solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(30 mg, 0.060 mmol), 5-cyanothiophen-2-ylboronic acid (27.5 mg, 0.180mmol), tris(dibenzylideneacetone)dipalladium(0) (3.29 mg, 3.59 μmol) and2-(dicyclohexylphosphino)biphenyl (1.259 mg, 3.59 μmol) in dioxane (2mL) and DMF (0.500 mL) was heated to 160° C. via microwave irradiationfor 60 minutes. The reaction mixture was diluted with EtOAc (50 mL) andsaturated aqueous NaHCO₃ (100 mL). The organic layer was separated andthe aqueous layer was washed with EtOAc (50 mL). The combined organiclayers were dried over Na₂SO₄ and the solvent was removed in vacuo togive the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(5-cyanothiophen-2-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dispersed in TFA and DCM (10 mL). The mixture wasstirred at room temperature for 60 minutes and then concentrated. Theresulting crude material was reconstituted in MeOH and DCM (10.0 mL) andwas purified via preparative HPLC, eluting with a gradient of 20-25% ACN(0.035% TFA) and H₂O (0.05% TFA). The collected fractions were combinedand the solvent was stripped to dryness via rotary evaporation to yielda TFA salt of the title compound (3.3 mg, 15%). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.78 (d, J=14.16 Hz, 1H), 2.04-2.21 (m, 1H), 3.57-3.67(m, 1H), 3.73-3.88 (m, 2H), 4.01 (d, J=10.74 Hz, 2H), 4.36 (d, J=11.23Hz, 1H), 4.48 (br s, 2H), 7.47 (br s, 1H), 7.91-8.02 (m, 3H), 8.73 (brs, 1H), 9.13 (br s, 1H). ESI-MS m/z [M+H]⁺calc'd for C₁₂H₁₆FN₅O₂S, 374.found, 374.

Example 96-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A TFA salt of the title compound was prepared in a manner similar toExample 7 using thieno[2,3-c]pyridin-2-ylboronic acid in place of5-fluorobenzo[b]thiophen-2-ylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δppm 1.74-1.91 (m, 1H), 2.12-2.26 (m, 1H), 3.59-3.69 (m, 1H), 3.77-3.95(m, 2H), 4.00-4.13 (m, 2H), 4.42 (d q, J=12.75, 4.37 Hz, 1H), 4.53 (d,J=5.37 Hz, 2H), 7.61 (br s, 1H), 8.07 (br s, 2H), 8.21 (br s, 1H), 8.60(d, J=5.86 Hz, 1H), 8.82 (s, 1H), 9.47 (br s, 1H), 9.61 (s, 1H). ESI-MSm/z [M+H]⁺calc'd for C₁₉H₁₈FN₅O₂S, 400. found, 400.

Example 106-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(53 mg, 0.106 mmol), 2-(tributylstannyl)thieno[2,3-c]pyridine (44.9 mg,0.106 mmol) and tetrakis(triphenylphosphine) palladium(0) (122 mg, 0.106mmol) in toluene (3 mL) was heated to 120° C. in a microwave for 60minutes. The reaction mixture was diluted with EtOAc (50 mL) andsaturated aqueous NaHCO₃ (100 mL). The organic layer was separated andthe aqueous layer was washed with EtOAc (50 mL). The organic layers werecombined and dried over Na₂SO₄, and the solvent was removed in vacuo togive the intermediate, ten-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dispersed in TFA and DCM (10 mL). The mixture wasstirred at room temperature for 60 minutes and then concentrated. Theresulting crude material was reconstituted in MeOH and DCM (10.0 mL) andpurified via preparative HPLC, eluting with a gradient of 10-25% ACN(0.035% TFA) and H₂O (0.05% TFA). The collected fractions were combinedand diluted with EtOAc (50 mL) and saturated aqueous NaHCO₃ (100 mL).The organic layer was separated and the aqueous layer was extracted withEtOAc (50 mL). The organic layers were combined and dried over Na₂SO₄,and the solvent was removed in vacuo to give the title compound (5.8 mg,14%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.83 (d, J=8.79 Hz, 1H), 2.10-2.27(m, 1H), 3.81-3.92 (m, 2H), 3.98-4.16 (m, 3H), 4.34-4.48 (m, 1H), 4.52(br s, 2H), 7.55 (d, J=5.37 Hz, 1H), 7.97-8.08 (m, 3H), 8.53 (br s, 1H),8.75 (s, 1H), 9.34 (br s, 1H), 9.53 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₁₉H₁₈FN₅O₂S, 400. found, 400.

Example 115-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiophene-2-carbonitrile

A TFA salt of the title compound was prepared in a manner similar toExample 7 using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitrilein place of 5-fluorobenzo[b]thiophen-2-ylboronic acid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.78 (d, J=12.69 Hz, 1H), 2.03-2.22 (m, 2H), 3.69-3.87(m, 2H), 4.01 (d, J=12.20 Hz, 2H), 4.26-4.41 (m, 1H), 4.43-4.53 (m, 2H),7.44 (d, J=5.37 Hz, 1H), 7.96 (br s, 2H), 8.63-8.68 (m, 1H), 8.71 (s,1H), 9.29 (s, 1H). ESI-MS m/z [M+H]⁺calc'd for C₁₇H₁₆FN₅O₂S, 374. found,374.

Example 126-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(5-fluorothiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A TFA salt of the title compound was prepared in a manner similar toExample 7 using2-(5-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane inplace of 5-fluorobenzo[b]thiophen-2-ylboronic acid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.72-1.81 (m, 1H), 3.56-3.66 (m, 1H), 3.77 (d, J=11.72Hz, 2H), 3.94-4.14 (m, 3H), 4.25-4.33 (m, 1H), 4.38-4.52 (m, 2H),6.74-6.81 (m, 1H), 7.32 (s, 1H), 7.92 (br s, 2H), 8.55 (s, 1H), 8.80 (t,J=4.15 Hz, 1H). ESI-MS m/z [M+H]⁺calc'd for C₁₆H₁₆F₂N₄O₂S, 367. found,367.

Example 136-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[2,3-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

The title compound was prepared in a manner similar to Example 10 using2-(tributylstannyl)thieno[2,3-b]pyridine in place of2-(tributylstannyl)thieno[2,3-c]pyridine. ¹H NMR (500 MHz, DMSO-d₆) δppm 1.82 (d, J=9.76 Hz, 1H), 2.07-2.23 (m, 1H), 3.62-3.70 (m, 1H), 3.83(d, J=11.23 Hz, 1H), 3.92 (br s, 2H), 4.00-4.10 (m, 2H), 4.34-4.42 (m,1H), 4.49 (s, 2H), 7.37-7.53 (m, 1H), 7.99 (d, J=4.39 Hz, 2H), 8.32 (dd,J=8.06, 1.71 Hz, 1H), 8.51-8.61 (m, 1H), 8.63-8.76 (m, 1H), 9.43 (s,1H). ESI-MS m/z [M+H]⁺calc'd for C₁₉H₁₈FN₅O₂S, 400. found, 400.

Example 146-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[2,3-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

STEP A: tert-Butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(thieno[2,3-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

A solution of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(200 mg, 0.401 mmol), 2-(tributylstannyl)thieno[2,3-b]pyridine (340 mg,0.802 mmol) and tetrakis(triphenylphosphine)palladium(0) (463 mg, 0.401mmol) in toluene (3 mL) was heated to 102° C. overnight. The reactionmixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO₃ (100mL). The organic layer was separated and the aqueous layer was washedwith EtOAc (50 mL). The organic layers were combined, dried over Na₂SO₄,and the solvent was removed in vacuo. The crude product was purified bysilica gel column chromatography, eluting with a gradient of 5-50% EtOAcand hexane over a period of 120 minutes. The fractions were collected togive the title compound (85 mg, 35%). ESI-MS m/z [M+H]⁺calc'd forC₃₀H₃₆FN₅O₅S, 598. found, 598.

STEP B:6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[2,3-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a solution of tert-butyl6-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(thieno[2,3-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(85 mg, 142 mmol) in DCM (3 mL) was added 4M HCl (10 mL). The reactionmixture was stirred at 60° C. for 1 hour. After removal of the solvent,the resulting crude material was reconstituted in MeOH/DMF/DCM (10.0 mL)and was purified via preparative mass trigger LCMS, eluting with agradient of 20-25% ACN (0.035% TFA) and H₂O (0.05% TFA). The collectedfractions were combined and the solvent was stripped to dryness viarotary evaporation to give a TFA salt of the title compound (13 mg, 8%two steps). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.39-2.08 (m, 8H), 3.88 (brs, 1H), 4.31 (d, J=3.91 Hz, 1H), 4.44-4.56 (m, 2H), 7.11-7.22 (m, 1H),7.38-7.46 (m, 1H), 7.79 (br s, 2H), 8.32 (dd, J=8.05, 1.71 Hz, 1H), 8.57(dd, J=4.64, 1.71 Hz, 1H), 8.68 (s, 1H), 9.43 (s, 1H). ESI-MS m/z[M+H]⁺calc'd for C₂₀H₂₀FN₅OS, 398. found, 398.

Example 156-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

STEP A: tert-Butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

A solution of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(200 mg, 0.401 mmol), 2-(tributylstannyl)thieno[2,3-c]pyridine (510 mg,1.202 mmol) and tetrakis(triphenylphosphine)palladium(0) (463 mg, 0.401mmol) in toluene (3 mL) was heated to 120° C. via microwave irradiationfor 30 minutes. The reaction mixture was diluted with EtOAc (50 mL) andsaturated aqueous NaHCO₃ (100 mL). The organic layer was separated andthe aqueous layer was washed with EtOAc (50 mL). The organic layers werecombined, dried over Na₂SO₄, and the solvent was removed in vacuo. Thecrude product was purified by silica gel column chromatography, elutingwith a gradient of 5-50% EtOAc and hexane over a period of 120 minutes.The fractions were collected to give the title compound (135 mg, 56%).

STEP B:6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a solution of tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(135 mg, 226 mmol) in DCM (3 mL) was added TFA in DCM (1:1, 10 mL). Thereaction mixture was stirred at room temperature for 1 hour. Afterremoval of the solvent, the resulting crude material was reconstitutedin MeOH/DMF/DCM (10.0 mL) and was purified via preparative mass triggerLCMS, eluting with a gradient of 10-25% ACN (0.035% TFA) and H₂O (0.05%TFA). The collected fractions were combined and the solvent was strippedto dryness via rotary evaporation to give a TFA salt of the titlecompound (76 mg, 48% two steps). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.48-2.06 (m, 8H), 3.83 (br s, 1H), 4.34 (d, J=3.28 Hz, 1H), 4.57 (s,2H), 7.35 (d, J=6.06 Hz, 1H), 7.88 (br s, 2H), 8.20 (d, J=5.81 Hz, 1H),8.58 (d, J=5.81 Hz, 1H), 8.81 (s, 1H), 9.47 (s, 1H), 9.61 (s, 1H).ESI-MS m/z [M+H]⁺calc'd for C₂₀H₂₀FN₅OS, 398. found, 398.

Example 166-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A solution of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(300 mg, 0.601 mmol), 5-fluorobenzo[b]thiophen-2-ylboronic acid (236 mg,1.202 mmol) and tetrakis(triphenylphosphine)palladium(0) (695 mg, 0.601mmol) in dioxane and saturated aqueous NaHCO₃ (1:1, 5 mL) was heated to120° C. via microwave irradiation for 30 minutes. After the solvent wasremoved, the crude product was purified by silica gel columnchromatography, eluting with a gradient of 10-50% EtOAc and hexane overa period of 60 minutes. The fractions were collected to give theintermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was first dissolved in DCM (3 mL) then TFA/DCM (1:1, 10mL) and the mixture was stirred at 60° C. for 1 hour. After solvent wasremoved, the resulting crude material was reconstituted in MeOH/DMF/DCM(30.0 mL) and purified via preparative mass trigger LCMS, eluting withgradient of 30-40 ACN (0.035% TFA) and H₂O (0.05% TFA). The collectedfractions were combined and ACN was removed via rotary evaporation. Themixture was neutralized with saturated aqueous NaHCO₃, washed with EtOAc(2×300 mL), dried over Na₂SO₄, and filtered. The organic phase wasstripped to dryness via rotary evaporation to give the title compound(77 mg, 31%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36-2.09 (m, 8H), 3.82(br s, 1H), 4.31 (d, J=1.95 Hz, 1H), 4.42-4.53 (m, 2H), 7.13 (d, J=5.86Hz, 1H), 7.27 (td, J=8.91, 2.69 Hz, 1H), 7.56-7.82 (m, 3H), 7.94-8.04(m, 1H), 8.64 (s, 1H), 9.41 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂₁H₂₀F₂N₄OS, 415. found, 415.

Example 176-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[3,2-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

The title compound was prepared in a manner similar to Example 10 using2-(tributylstannyl)thieno[3,2-c]pyridine in place of2-(tributylstannyl)thieno[2,3-c]pyridine. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.82 (d, J=9.35 Hz, 1H), 2.09-2.27 (m, 1H), 3.57-3.69 (m, 1H),3.80-3.93 (m, 2H), 3.96-4.17 (m, 2H), 4.40 (td, J=8.53, 4.42 Hz, 1H),4.52 (d, J=2.78 Hz, 2H), 7.60 (d, J=5.31 Hz, 1H), 8.09 (d, J=4.29 Hz,2H), 8.39 (d, J=5.31 Hz, 1H), 8.58 (d, J=6.06 Hz, 1H), 8.80 (s, 1H),9.46 (s, 1H), 9.71 (s, 1H). ESI-MS m/z [M+H]⁺calc'd for C₁₉H₁₈FN₅O₂S,400. found, 400.

Example 186-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[3,2-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(200 mg, 0.399 mmol), 2-(tributylstannyl)thieno[3,2-c]pyridine (339 mg,0.798 mmol) and tetrakis(triphenylphosphine)palladium(0) (461 mg, 0.399mmol) in toluene (3 mL) was heated to 120° C. via microwave irradiationfor 30 minutes. After the solvent was removed, the crude product waspurified by silica gel column chromatography, eluting with a gradient of10-50% EtOAc and hexane over a period of 60 minutes. The fractions werecollected to give the intermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(thieno[3,2-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was first dissolved in DCM (3 mL) and then TFA/DCM(1:1, 10 mL) at 60° C. for 1 hour. After removal of solvent, theresulting crude material was reconstituted in MeOH/DMF/DCM (30.0 mL) andpurified via preparative mass triggered LCMS, eluting with a gradient of30-40% ACN (0.035% TFA) and H₂O (0.05% TFA). The collected fractionswere combined and the ACN was removed via rotary evaporation. Themixture was neutralized with saturated aqueous NaHCO₃, washed with EtOAc(2×300 mL), dried over Na₂SO₄, and filtered. The organic phase wasstripped to dryness via rotary evaporation to give the title compound(30 mg, 19%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44-2.10 (m, 8H), 3.82(br s, 1H), 4.33 (d, J=3.54 Hz, 1H), 4.47 (s, 2H), 7.30 (d, J=6.06 Hz,1H), 7.89 (br s, 2H), 8.39 (d, J=5.05 Hz, 1H), 8.57 (s, 1H), 8.77 (s,1H), 9.44 (s, 1H), 9.71 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂₀H₂₀FN₅OS, 398. found, 398.

Example 196-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(6-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A TFA salt of the title compound was prepared in a manner similar toExample 7 using 6-fluorobenzo[b]thiophen-2-ylboronic acid in place of5-fluorobenzo[b]thiophen-2-ylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δppm 1.82 (d, J=9.28 Hz, 1H), 2.15 (qd, J=12.86, 4.88 Hz, 1H), 3.59-3.69(m, 1H), 3.78-3.94 (m, 2H), 4.00-4.11 (m, 2H), 4.34-4.42 (m, 1H), 4.47(s, 2H), 7.20-7.30 (m, 1H), 7.41 (d, J=4.88 Hz, 1H), 7.81-7.90 (m, 1H),7.91-8.00 (m, 3H), 8.62-8.69 (m, 1H), 9.38-9.50 (m, 1H). ESI-MS m/z[M+H]⁺calc'd for C₂₀H₁₈F₂N₄O₂S, 417. found, 417.

Example 206-(((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(6-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A TFA salt of the title compound was prepared in a manner similar toExample 16 using 6-fluorobenzo[b]thiophen-2-ylboronic acid in place of5-fluorobenzo[b]thiophen-2-ylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δppm 1.42-2.07 (m, 8H), 3.84 (br s, 1H), 4.32 (d, J=3.42 Hz, 1H), 4.48(d, J=4.39 Hz, 2H), 7.11 (br s, 1H), 7.25 (td, J=9.03, 2.44 Hz, 1H),7.80 (br s, 2H), 7.88 (dd, J=9.28, 2.44 Hz, 1H), 7.94 (dd, J=8.79, 5.37Hz, 1H), 8.63 (s, 1H), 9.43 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂H₂₀F₂N₄OS, 415. found, 415.

Example 212-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzo[b]thiophene-5-carbonitrile

A solution of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(100 mg, 0.200 mmol), 5-cyanobenzo[b]thiophen-2-ylboronic acid (40.5 mg,0.200 mmol) and tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.200mmol) in dioxane and saturated aqueous Na₂CO₃ (3:5, 6 mL) was heated to120° C. in a microwave for 30 minutes. The reaction mixture was dilutedwith EtOAc (50 mL) and saturated aqueous NaHCO₃ (100 mL). The organiclayer was separated and the aqueous layer was washed with EtOAc (50 mL).The organic layers were combined, dried over Na₂SO₄, and the solvent wasremoved in vacuo to give the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(5-cyanobenzo[b]thiophen-2-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dispersed in TFA and DCM (1:1, 10 mL) and themixture was stirred at room temperature for 60 minutes. The mixture wasconcentrated, reconstituted in MeOH and DCM (10.0 mL) and purified viapreparative HPLC eluting with a gradient of 10-25% ACN (0.035% TFA) andH₂O (0.05% TFA). The collected fractions were combined and diluted withEtOAc (50 mL) and saturated aqueous NaHCO₃ (100 mL). The organic layerwas separated and the aqueous layer was washed with EtOAc (50 mL). Theorganic layers were combined, dried over Na₂SO₄, and the solvent wasremoved in vacuo to give the title compound (26 mg, 31%). ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.78 (dd, J=13.42, 4.15 Hz, 1H), 1.87-2.05 (m, 1H),3.17-3.25 (m, 1H), 3.45-3.57 (m, 1H), 3.67 (d, J=10.25 Hz, 1H), 3.80 (brs, 1H), 3.91 (d, J=11.23 Hz, 1H), 4.26 (d, J=4.39 Hz, 1H), 4.43 (s, 2H),7.00 (d, J=6.35 Hz, 1H), 7.72 (dd, J=8.30, 1.46 Hz, 1H), 8.20 (d, J=8.30Hz, 1H), 8.47 (d, J=1.46 Hz, 1H), 8.61 (s, 1H), 9.50 (s, 1H). ESI-MS m/z[M+H]⁺calc'd for C₂₁H₁₈FN₅O₂S, 424. found, 424.

Example 222-(6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzo[b]thiophene-5-carbonitrile

A TFA salt of the title compound was prepared in a manner similar toExample 16 using 5-cyanobenzo[b]thiophen-2-ylboronic acid in place of5-fluorobenzo[b]thiophen-2-ylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δppm 1.38-2.07 (m, 8H), 3.83 (br s, 1H), 4.33 (d, J=3.42 Hz, 1H),4.47-4.56 (m, 2H), 7.19 (d, J=5.86 Hz, 1H), 7.72-7.77 (m, 1H), 7.80 (d,J=4.39 Hz, 2H), 8.21 (d, J=8.79 Hz, 1H), 8.49 (d, J=0.98 Hz, 1H), 8.69(s, 1H), 9.51 (s, 1H). ESI-MS m/z [M+H]⁺calc'd for C₂₂H₂₀FN₅OS, 422.found, 422.

Example 236-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(4-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A TFA salt of the title compound was prepared in a manner similar toExample 7 using 4-fluorobenzo[b]thiophen-2-ylboronic acid in place of5-fluorobenzo[b]thiophen-2-ylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δppm 1.82 (d, J=9.76 Hz, 1H), 2.08-2.24 (m, 1H), 3.60-3.71 (m, 1H),3.81-3.88 (m, 1H), 3.91 (br s, 1H), 4.00-4.12 (m, 2H), 4.34-4.43 (m,1H), 4.49 (s, 2H), 7.17-7.26 (m, 1H), 7.36-7.50 (m, 2H), 7.80 (s, 1H),7.98 (br s, 2H), 8.69 (s, 1H), 9.52-9.63 (m, 1H). ESI-MS m/z[M+H]⁺calc'd for C₂₀H₁₅F₂N₄O₂S, 417. found, 417.

Example 246-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(4-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A solution of tert-butyl6-(((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(152 mg, 0.305 mmol), 4-fluorobenzo[b]thiophen-2-ylboronic acid (149 mg,0.762 mmol) and tetrakis(triphenylphosphine)palladium(0) (352 mg, 0.305mmol) in dioxane and saturated aqueous NaHCO₃ (1:1, 5 mL) was heated to120° C. via microwave irradiation for 30 minutes. The reaction mixturewas diluted with EtOAc (50 mL) and saturated aqueous NaHCO₃ (100 mL).The organic layer was separated and the aqueous layer was washed withEtOAc (50 mL). The organic layers were combined, dried over Na₂SO₄, andthe solvent was removed in vacuo to give the intermediate, tert-butyl6-((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(4-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dispersed in TFA and DCM (1:1, 10 mL) and stirredat room temperature for 60 minutes. The mixture was concentrated and theresulting crude material was reconstituted in MeOH/DCM (10.0 mL) and waspurified via preparative HPLC eluting with a gradient of 30-50% ACN(0.035% TFA) and H₂O (0.05% TFA). The combined fractions wereneutralized with saturated aqueous NaHCO₃, washed with EtOAc (2×200 mL),dried over Na₂SO₄, and filtered. The organic phase was stripped todryness via rotary evaporation to give the title compound (83 mg, 66%).¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.31-1.48 (m, 2H), 1.55-1.85 (m, 6H),3.17 (s, 2H), 4.10 (dd, J=6.35, 2.93 Hz, 2H), 4.45 (s, 2H), 6.79 (d,J=6.35 Hz, 1H), 7.19 (dd, J=10.25, 7.81 Hz, 1H), 7.40 (td, J=8.05, 5.37Hz, 1H), 7.82 (d, J=8.30 Hz, 1H), 8.56 (s, 1H), 9.56 (s, 1H). ESI-MS m/z[M+H]⁺calc'd for C₂₁H₂₀F₂N₄OS, 415. found, 415.

Example 256-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[3,2-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

The title compound was prepared in a manner similar to Example 21 usingthieno[3,2-b]pyridin-2-ylboronic acid in place of5-cyanobenzo[b]thiophen-2-ylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δppm 1.62-2.06 (m, 4H), 3.09 (d, J=1.95 Hz, 1H), 3.43-3.53 (m, 1H), 3.63(dd, J=11.72, 1.95 Hz, 1H), 3.76 (dd, J=11.72, 2.44 Hz, 1H), 3.89 (dt,J=11.35, 3.60 Hz, 1H), 4.20-4.29 (m, 1H), 4.47 (s, 2H), 6.89 (d, J=6.83Hz, 1H), 7.36 (dd, J=8.05, 4.64 Hz, 1H), 8.39-8.49 (m, 1H), 8.55-8.71(m, 2H), 9.58 (s, 1H). ESI-MS m/z [M+H]⁺calc'd for C₁₉H₁₈FN₅O₂S, 400.found, 400.

Example 266-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[3,2-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

The title compound was prepared in a manner similar to Example 24 usingthieno[3,2-b]pyridin-2-ylboronic acid in place of4-fluorobenzo[b]thiophen-2-ylboronic acid. ¹H NMR (500 MHz, DMSO-d₆) δppm 1.24 (s, 1H), 1.40 (br s, 3H), 1.55-1.87 (m, 7H), 3.21 (d, J=2.93Hz, 1H), 4.08 (d, J=3.42 Hz, 1H), 4.37-4.52 (m, 2H), 6.75 (br s, 1H),7.25-7.38 (m, 1H), 8.39-8.48 (m, 1H), 8.58 (s, 1H), 8.65 (dd, J=4.39,1.46 Hz, 1H), 9.54 (s, 1H). ESI-MS m/z [M+H]⁺calc'd for C₂₀H₂₀FN₅OS,398. found, 398.

Example 276-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(4-fluorothiophene-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a 30 mL sealed cap glass vessel containing tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(200 mg, 0.399 mmol) and2-(4-fluorothiophene-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137mg, 0.599 mmol) dissolved in DME and water (4:1) was addedtetrakis(triphenylphosphine)palladium(0) (105 mg, 0.399 mmol) andpotassium phosphate, tribasic (212 mg, 1 mmol). The cap was sealed, andthe reaction mixture was heated at 85° C. for 1 hour and then cooled toroom temperature. The mixture was diluted with water (10 mL) andextracted with EtOAc (2×25 mL). The organic layers were combined, driedover sodium sulfate, and solvent removed via rotary evaporation to givethe intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(4-fluorothiophene-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in TFA (5 mL) and the resulting mixturewas stirred at room temperature for 1 hour to give crude product, whichwas purified via preparative HPLC, eluting with a gradient of 15-50% ACN(0.035% TFA) and H₂O (0.05% TFA). The pure fractions were combined,evaporated to minimal volume, and lyophilized to give a TFA salt of thetitle compound (86 mg, 59%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.78 (d,J=9.60 Hz, 1H), 2.03-2.18 (m, 1H), 3.53-3.68 (m, 1H), 3.75 (d, J=11.62Hz, 1H), 3.85 (br s, 1H), 4.01 (d, J=12.38 Hz, 2H), 4.32 (td, J=8.53,4.17 Hz, 1H), 4.45 (s, 2H), 7.32 (t, J=1.64 Hz, 1H), 7.40 (d, J=5.31 Hz,1H), 7.95 (br s, 3H), 8.65 (s, 1H), 8.98 (d, J=1.77 Hz, 1H). ESI-MS m/z[M+H]⁺calc'd for C₁₆H₁₆F₂N₄O₂S, 367. found, 367.

Example 286-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(4-fluorothiophene-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a 30 mL sealed cap glass vessel containing tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(200 mg, 0.401 mmol) and2-(4-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137mg, 0.601 mmol) dissolved in DME and water (4:1) was addedtetrakis(triphenylphosphine)palladium(0) (105 mg, 0.401 mmol) andpotassium phosphate, tribasic (212 mg, 1 mmol). The cap was sealed, andthe reaction mixture was heated at 85° C. for 4 hours and then cooled toroom temperature. The mixture was diluted with water and extracted withEtOAc (2×25 mL). The organic layers were combined, dried over sodiumsulfate, and evaporated to give the intermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(4-fluorothiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in TFA (5 mL) and stirred at roomtemperature for 2 hours. The mixture was evaporated and purified bypreparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) andH₂O (0.05% TFA). The pure fractions were combined, evaporated to minimalvolume, and lyophilized to give a TFA salt of the title compound as awhite solid (112 mg, 77%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29-1.54 (m,2H), 1.60 (d, J=12.88 Hz, 2H), 1.66-1.81 (m, 2H), 1.83-1.99 (m, 2H),3.81 (br s, 1H), 4.24 (br s, 1H), 4.45 (d, J=2.27 Hz, 2H), 7.14 (d,J=5.31 Hz, 1H), 7.31 (t, J=1.39 Hz, 1H), 7.79 (br s, 3H), 8.62 (s, 1H),8.97 (d, J=1.77 Hz, 1H). ESI-MS m/z [M+H]⁺calc'd for C₁₂H₁₈F₂N₄OS, 365.found, 365.

Example 296-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass vessel, tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(102 mg, 0.205 mmol),1-methyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (175 mg, 0.410mmol) and tetrakis(triphenylphosphine) palladium(0) (118 mg, 0.102 mmol)were dissolved in toluene (5 mL). The cap was sealed and the reactionmixture was heated at 90° C. in an oil bath for 2 hours. The reactionmixture was concentrated to give the intermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in TFA (5 mL) and the reaction mixturewas stirred for 1 hour. The mixture was concentrated, dissolved in DMSO(5 mL), and purified via preparative HPLC, eluting with a gradient of15-65% ACN (0.035% TFA) and H₂O (0.05% TFA). The pure fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a white solid (75 mg, 91%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.28-1.55 (m, 2H), 1.60 (d, J=14.15 Hz, 1H),1.67-1.93 (m, 3H), 1.98 (dd, J=13.64, 4.29 Hz, 2H), 3.85 (br s, 1H),3.99 (s, 2H), 4.24 (d, J=3.54 Hz, 1H), 4.38-4.54 (m, 2H), 7.14 (d,J=5.81 Hz, 1H), 7.62-7.88 (m, 3H), 8.62 (s, 1H), 9.27 (s, 1H). ESI-MSm/z [M+H]⁺calc'd for C₁₉H₂₁FN₆OS, 401. found, 401.

Example 306-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass vessel, tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(119 mg, 0.238 mmol),1,3-dimethyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (210 mg, 0.476mmol) and tetrakis(triphenylphosphine)palladium(0) (137 mg, 0.119 mmol)were dissolved in toluene (5 mL). The cap was sealed and the reactionmixture was heated at 90° C. in an oil bath for 2 hours. The mixture wasconcentrated to give the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in TFA (5 mL) and the reaction mixturewas stirred for 1 hour. The mixture was concentrated, dissolved in DMSO(5 mL), and purified via preparatory HPLC eluting with a gradient of15-50% ACN (0.035% TFA) and H₂O (0.05% TFA). The pure fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a white solid (65 mg, 68%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.79 (d, J=10.86 Hz, 1H), 2.04-2.26 (m, 1H),3.55-3.68 (m, 2H), 3.80 (d, J=11.62 Hz, 1H), 3.89 (br s, 1H), 3.99 (s,3H), 4.02-4.06 (m, 1H), 4.33 (td, J=8.27, 4.67 Hz, 1H), 4.45 (s, 2H),7.40 (d, J=5.05 Hz, 1H), 7.74 (d, J=0.76 Hz, 1H), 7.96 (d, J=4.55 Hz,2H), 8.65 (s, 1H), 9.28 (d, J=0.76 Hz, 1H). ESI-MS m/z [M+H]⁺calc'd forC₁₈H₁₉FN₆O₂S, 403. found, 403.

Example 316-((1R,2S)-2-Aminocyclohexylamino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass tube, tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.301 mmol),1,3-dimethyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (265 mg, 0.601mmol) and tetrakis(triphenylphosphine) palladium(0) (174 mg, 0.150 mmol)were dissolved in toluene (5 mL). The cap was sealed and the reactionmixture was heated at 90° C. in an oil bath for 2 hours. The mixture wasconcentrated to give the intermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in TFA (5 mL) and the reaction mixturewas stirred for 2 hours. The mixture was concentrated, dissolved in DMSO(5 mL), and purified via preparatory HPLC eluting with a gradient of15-65% ACN (0.035% TFA) and H₂O (0.05% TFA). The pure fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a white solid (95 mg, 72%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.48 (br s, 2H), 1.43-2.03 (m, 6H), 2.33 (s, 3H),3.83 (br s, 1H), 3.90 (s, 3H), 4.28 (br s, 1H), 4.39-4.51 (m, 2H), 7.09(d, J=5.81 Hz, 1H), 7.79 (br s, 3H), 8.61 (s, 1H), 9.22 (s, 1H). ESI-MSm/z [M+H]⁺calc'd for C₂₀H₂₃FN₆OS, 415. found, 415.

Example 326-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass tube, tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(119 mg, 0.238 mmol),1,3-dimethyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (210 mg, 0.476mmol) and tetrakis(triphenylphosphine)palladium(0) (137 mg, 0.119 mmol)were dissolved in toluene (5 mL). The cap was sealed and the reactionmixture was heated at 90° C. in an oil bath for 2 hours. The mixture wasconcentrated to give the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in TFA (5 mL) and the reaction mixturewas stirred for 2 hours. The mixture was concentrated, dissolved in DMSO(5 mL), and purified via preparatory HPLC eluting with a gradient of15-65% ACN (0.035% TFA) and H₂O (0.05% TFA). The pure fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a white solid (101 mg, 76%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.79 (d, J=9.60 Hz, 1H), 2.02-2.22 (m, 1H), 2.33 (brs, 3H), 3.55-3.71 (m, 1H), 3.82 (d, J=11.62 Hz, 1H), 3.90 (br s, 3H),3.97-4.13 (m, 2H), 4.27-4.40 (m, 1H), 4.41-4.53 (m, 2H), 7.24-7.44 (m,1H), 7.84-8.04 (m, 3H), 8.63 (br s, 1H), 9.22 (br s, 1H). ESI-MS m/z[M+H]⁺calc'd for C₁₉H₂₁FN₆O₂S, 417. found, 417.

Example 336-((1R,2S)-2-Aminocyclohexylamino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass tube, tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.301 mmol),2,3-dimethyl-5-(tributylstannyl)-2H-thieno[3,2-c]pyrazole (265 mg, 0.601mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol)were dissolved in toluene (5 mL). The cap was sealed and the reactionmixture was heated at 90° C. in an oil bath for 2 hours. The mixture wasconcentrated to give the intermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in TFA (5 mL) and the reaction mixturewas stirred for 90 minutes. The mixture was concentrated, dissolved inDMSO (5 mL), and purified via preparatory HPLC eluting with a gradientof 20-30% ACN (0.035% TFA) and H₂O (0.05% TFA). The pure fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a white solid (108 mg, 68.0%). ¹H NMR (400MHz, DMSO-d₆) ppm 1.49-2.04 (m, 8H), 2.45 (s, 3H), 3.84 (br s, 1H), 3.92(s, 3H), 4.27 (br s, 1H), 4.35-4.51 (m, 2H), 7.08 (d, J=6.06 Hz, 1H),7.78 (br s, 3H), 8.60 (s, 1H), 9.25 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂₀H₂₃FN₆OS, 415. found, 415.

Example 346-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass tube, tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(100 mg, 0.200 mmol),2,3-dimethyl-5-(tributylstannyl)-2H-thieno[3,2-c]pyrazole (176 mg, 0.399mmol) and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.100 mmol)were dissolved in toluene (5 mL). The cap was sealed and the reactionmixture was heated at 90° C. in an oil bath for 2 hours. The mixture wasconcentrated to give the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in TFA (5 mL) and the reaction mixturewas stirred for 2 hours. The mixture was concentrated, dissolved in DMSO(5 mL), and purified via preparatory HPLC eluting with a gradient of10-60% ACN (0.035% TFA) and H₂O (0.05% TFA). The pure fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a white solid (65 mg, 61%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.80 (d, J=12.38 Hz, 1H), 1.96-2.25 (m, 1H), 2.46(s, 3H), 3.55-3.71 (m, 1H), 3.82 (d, J=11.87 Hz, 1H), 3.92 (s, 3H), 4.05(d, J=11.12 Hz, 3H), 4.28-4.38 (m, 1H), 4.40-4.51 (m, 2H), 7.37 (d,J=4.80 Hz, 1H), 7.96 (d, J=4.80 Hz, 3H), 8.63 (s, 1H), 9.26 (s, 1H).ESI-MS m/z [M+H]⁺calc'd for C₁₉H₂₁FN₆O₂S, 417. found, 417.

Example 356-((1R,2S)-2-Aminocyclohexylamino)-4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass tube, tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.301 mmol),7-(tributylstannyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (124 mg,0.301 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150mmol) were dissolved in toluene (5 mL). The cap was sealed and thereaction mixture was heated at 90° C. in an oil bath for 2 hours.Following work-up, the intermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,was purified by preparative HPLC eluting with a gradient of 55-95% ACN(0.035% TFA) and H₂O (0.05% TFA). The pure fractions were combined andthe solvent stripped by rotary evaporation to give a solid intermediate.The intermediate was subsequently dissolved in TFA (3 mL) and thereaction mixture was stirred for 1 hour. The mixture was concentrated,dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting witha gradient of 20-50% ACN (0.035% TFA) and H₂O (0.05% TFA). The purefractions were combined, evaporated to a minimal volume, and lyophilizedto give a TFA salt of the title compound as a pale yellow solid (7.3 mg,6.3%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44 (d, J=7.33 Hz, 2H), 1.59 (brs, 1H), 1.63-1.92 (m, 4H), 3.98 (d, J=1.77 Hz, 3H), 4.26-4.46 (m, 3H),4.74 (s, 2H), 6.54-6.71 (m, 2H), 7.74 (br s, 3H), 8.17-8.36 (m, 2H).ESI-MS m/z [M+H]⁺calc'd for C₂₀H₂₄FN₅O₂, 386. found, 386.

Example 366-((1R,2S)-2-Aminocyclohexylamino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A mixture of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(120 mg, 0.240 mmol),1,3-dimethyl-5-(tributylstannyl)-1H-thieno[2,3-c]pyrazole (212 mg, 0.481mmol) and tetrakis(triphenylphosphine)palladium(0) (139 mg, 0.120 mmol)in toluene (3 mL) was heated to 120° C. in a Biotage Initiator microwavefor 30 minutes. The mixture was concentrated to give the intermediate,tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). Theresulting solution was stirred at room temperature for 20 minutes,concentrated, and purified by preparatory HPLC, eluting with a gradientof 10-40% ACN (0.035% TFA) and water (0.05% TFA). The collectedfractions were combined and dried to give a TFA salt of the titlecompound as a white solid (89 mg, 89%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.48-1.73 (m, 5H), 1.83-1.97 (m, 3H), 2.35 (s, 3H), 3.78-3.79 (m, 1H),3.86 (s, 3H), 4.26-4.27 (m, 1H), 4.43 (d, J=4.88 Hz, 2H), 7.02-7.04 (m,1H), 7.81-7.82 (m, 2H), 8.51 (s, 1H), 9.16 (s, 1H). ESI-MS m/z[M+H]⁺calc'd for C₂₀H₂₃FN₆OS, 415. found, 415.

Example 376-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A mixture of tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(200 mg, 0.399 mmol),1,3-dimethyl-5-(tributylstannyl)-1H-thieno[2,3-c]pyrazole (352 mg, 0.798mmol) and tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.200 mmol)in toluene (3 mL) was heated to 120° C. in a Biotage Initiator microwavefor 30 minutes. The mixture was concentrated to give the intermediate,tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). Theresulting solution was stirred at room temperature for 20 minutes,concentrated, and purified by preparatory HPLC, eluting with a gradientof 10-30% ACN (0.035% TFA) and water (0.05% TFA). The collectedfractions were combined and dried to give a TFA salt of the titlecompound as a white solid (85 mg, 51%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.79-1.81 (m, 1H), 2.13-2.14 (m, 1H), 2.53 (s, 3H), 3.61-3.63 (m, 1H),3.85-3.87 (m, 2H), 3.87 (s, 3H), 4.01-4.07 (m, 2H), 4.33-4.35 (m, 1H),4.44 (d, J=7.80 Hz, 2H), 7.33-47.34 (m, 1H), 8.01-8.02 (m, 2H), 8.53 (s,1H), 9.16 (s, 1H). ESI-MS m/z [M+H]⁺calc'd for C₁₉H₂₁FN₆O₂S, 417. found,417.

Example 386-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A mixture of bis(triphenylphosphine)palladium chloride (14.01 mg, 0.020mmol), tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(200 mg, 0.399 mmol), and1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (177mg, 0.798 mmol) in dioxane (4 mL) and saturated aqueous NaHCO₃ (1 mL)was heated to 100° C. in a Biotage Initiator microwave for 1 hour. Themixture was concentrated to give the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). Theresulting solution was stirred at room temperature for 20 minutes,concentrated, and purified by preparatory HPLC, eluting with a gradientof 10-25% ACN (0.035% TFA) and water (0.05% TFA). The collectedfractions were combined and dried to give a TFA salt of the titlecompound as a white solid (87 mg, 60%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.40 (t, J=7.3 Hz, 3H), 1.75-1.77 (m, 1H), 2.10-2.11 (m, 1H), 3.61-3.63(m, 1H), 3.85-3.86 (m, 1H), 3.93-3.94 (m, 1H), 3.96-3.98 (m, 2H), 4.18(q, J=7.32, 2H), 4.47-4.48 (m, 1H), 7.04-7.05 (m, 1H), 7.89-7.91 (m,2H), 8.30 (s, 1H), 8.37 (s, 1H), 8.88 (s, 1H). ESI-MS m/z [M+H]⁺calc'dfor C₁₂H₂₁FN₆O₂, 361. found, 361.

Example 39 Ethyl2-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carboxylate

A mixture of bis(triphenylphosphine)palladium chloride (13.09 mg, 0.019mmol), tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(187 mg, 0.373 mmol), and ethyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolizine-7-carboxylate(118 mg, 0.373 mmol) in dioxane (4 mL) and saturated aqueous NaHCO₃ (1mL) were heated to 100° C. in a Biotage Initiator microwave for 1 hour.The mixture was concentrated to give the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(7-(ethoxycarbonyl)indolizin-2-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). Theresulting solution was stirred at room temperature for 20 minutes,concentrated, and purified by preparatory HPLC, eluting with a gradientof 10-40% ACN (0.035% TFA) and water (0.05% TFA). The collectedfractions were combined and dried to give a TFA salt of the titlecompound as a tan solid (31 mg, 18%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34 (t, J=6.80 Hz, 3H), 1.78-1.81 (m, 1H), 2.11-2.12 (m, 1H), 3.62-3.65(m, 1H), 3.89-3.91 (m, 1H), 3.94-4.28 (m, 3H), 4.31 (q, J=6.83 Hz, 2H),4.43 (d, J=8.3 Hz, 2H), 4.53-4.54 (m, 1H), 6.96 (dd, J=1.46, 7.32 Hz,1H), 7.15 (d, J=4.88 Hz, 1H), 7.71 (s, 1H), 7.92-7.93 (m, 2H), 8.21 (s,1H), 8.36 (d, J=7.32 Hz, 1H), 8.48 (s, 1H), 9.03 (s, 1H). ESI-MS m/z[M+H]⁺calc'd for C₂₃H₂₄FN₅O₄, 454. found, 454.

Example 402-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carboxylicacid

A mixture of ethyl2-(6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carboxylate(20 mg, 0.044 mmol) in dioxane (3 mL) and 1N NaOH (1 mL) was heated to150° C. in a Biotage Initiator microwave for 1 hour. The mixture wasconcentrated under reduced pressure and purified by preparatory HPLC,eluting with a gradient of 10-30% ACN (0.035% TFA) and water (0.05%TFA). The collected fractions were combined and dried to give a TFA saltof the title compound as a yellow solid (8 mg, 43%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.79-1.81 (m, 1H), 2.11-2.12 (m, 1H), 3.65-3.67 (m, 1H),3.93-4.04 (m, 4H), 4.43 (d, J=7.8 Hz, 2H), 4.52-4.53 (m, 1H), 6.95 (dd,J=1.46, 7.32 Hz, 1H), 7.14 (d, J=4.88 Hz, 1H), 7.67 (s, 1H), 7.92-7.93(m, 2H), 8.16 (s, 1H), 8.34 (d, J=7.32 Hz, 1H), 8.47 (s, 1H), 9.00 (s,1H). ESI-MS m/z [M+H]⁺calc'd for C₂₁H₂₀FN₅O₄, 426. found, 426.

Example 416-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(1-oxo-2,3-dihydro-1H-pyrrolizin-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A mixture of bis(triphenylphosphine)palladium chloride (10.51 mg, 0.015mmol), tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.299 mmol), and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolizin-1-one(148 mg, 0.599 mmol) in dioxane (4 mL) and saturated aqueous NaHCO₃ (1mL) was heated to 100° C. in a Biotage Initiator microwave for 1 hour.The mixture was concentrated to give the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-(1-oxo-2,3-dihydro-1H-pyrrolizin-6-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). Theresulting solution was stirred at room temperature for 20 minutes,concentrated, and purified by preparatory HPLC, eluting with a gradientof 10-40% ACN (0.035% TFA) and water (0.05% TFA). The collectedfractions were combined and dried to give a TFA salt of the titlecompound as a white solid (7 mg, 6%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.75-1.78 (m, 1H), 2.10-2.11 (m, 1H), 3.01-3.04 (m, 2H), 3.34-3.34 (m,1H), 3.66-3.67 (m, 1H), 3.76-3.78 (m, 1H), 3.84-3.86 (m, 1H), 3.95-3.97(m, 1H), 4.37-4.39 (m, 4H), 4.50-4.51 (m, 1H), 7.05 (d, J=6.35 Hz, 1H),7.60 (s, 1H), 7.90-7.92 (m, 2H), 8.43 (s, 1H), 8.56 (s, 1H). ESI-MS m/z[M+H]⁺calc'd for C₁₉H₂₀FN₅O₃, 386. found, 386.

Example 426-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(3-methylisothiazol-5-yl)-1H-pyaolo[3,4-c]pyridin-3(2H)-one

To a stirred solution of tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-7-fluoro-4-(3-methylisothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(82 mg, 0.146 mmol) in MeOH (2.0 mL) was added 4N HCl/dioxane (2.0 mL,8.00 mmol). The reaction mixture was heated to 60° C. for 1 hour.Following reaction, the mixture was concentrated in vacuo. The residuewas triturated with EtOAc and filtered. The filter cake was washed withEtOAc to yield crude desired compound as a yellow solid. The crudeproduct was recrystallized from MeOH-Et₂O to give a hydrochloride saltof the title compound as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.37-1.56 (m, 2H), 1.58-1.83 (m, 4H), 1.84-2.04 (m, 2H), 2.46 (s, 3H),3.73 (br. s., 1H), 4.17-4.29 (m, 1H), 4.47 (s, 2H), 7.17 (d, J=5.37 Hz,1H), 7.84 (br. s., 3H), 8.66 (s, 1H), 8.76 (s, 1H). ESI-MS m/z[M+H]⁺calc'd for C₁₇H₂₀FN₅OS, 362. found, 362.

Example 436-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL glass vial, tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.301 mmol),4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane (103 mg, 0.451mmol) and PdCl₂(PPh₃)₂ (105 mg, 0.150 mmol) were dissolved in dioxane (5mL). To the reaction mixture was added 2N aqueous sodium carbonatesolution (2 mL). The vessel was sealed with a cap and the reactionmixture was heated at 90° C. for 2 hours. The reaction mixture wassubsequently diluted with water (10 mL) and was extracted with EtOAc(2×50 mL). The combined organic phase was dried over sodium sulfate andevaporated to give the intermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in dichloromethane (3 mL), TFA (3 mL) wasadded, and the mixture was stirred for 1 hour. The volatiles weresubsequently evaporated and the residual material was dissolved in DMSO(5 mL) and purified by preparative HPLC, eluting with a gradient of15-50% ACN (0.035% TFA) and water (0.05% TFA). The pure productfractions were combined, evaporated to a minimal volume, and lyophilizedto give a TFA salt of the title compound as a pale yellow solid (32 mg,29%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.43 (br s, 3H), 1.66-1.91 (m,5H), 3.63 (br s, 1H), 4.34-4.52 (m, 3H), 6.87 (d, J=7.07 Hz, 1H),7.41-7.52 (m, 3H), 7.56-7.65 (m, 2H), 7.74 (br s, 3H), 8.48 (s, 1H).ESI-MS m/z [M+H]⁺calc'd for C₂₁H₂₁FN₄O, 365. found, 365.

Example 446-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL glass vial, tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.299 mmol),4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane (75 mg, 0.329mmol) and PdCl₂(PPh₃)₂ (105 mg, 0.150 mmol) were dissolved in dioxane (5mL). To the reaction mixture was added 2N aqueous sodium carbonatesolution (2 mL). The vessel was sealed with a cap and the reactionmixture was heated to 90° C. in an oil bath for 2 hours. The reactionmixture was subsequently diluted with water (10 mL) and extracted withEtOAc (2×25 mL). The combined organic phase was dried over sodiumsulfate and evaporated to give the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in dichloromethane (3 mL), TFA (3 mL) wasadded, and the mixture was stirred for 1 hour. The volatiles weresubsequently evaporated and the residual material was dissolved in DMSO(5 mL) and purified by preparative HPLC, eluting with a gradient of15-50% ACN (0.035% TFA) and water (0.05% TFA). The pure productfractions were combined, evaporated to a minimal volume, and lyophilizedto give the TFA salt of the title compound as a pale yellow solid (14.5mg, 13%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72 (m, 1H), 2.05-2.12 (m,1H), 3.49-3.66 (m, 2H), 3.76 (d, J=11.62 Hz, 1H), 3.84-4.04 (m, 2H),4.31-4.51 (m, 3H), 7.16-7.29 (m, 1H), 7.42-7.53 (m, 3H), 7.53-7.67 (m,2H), 7.92 (br s, 3H), 8.50 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂₀H₁₉FN₄O₂, 367. found, 367.

Example 456-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(4-fluorostyryl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass vial, tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.301 mmol), (E)-4-fluorostyrylboronic acid (49.9 mg, 0.301mmol) and PdCl₂(PPh₃)₂ (42.2 mg, 0.060 mmol) were dissolved in dioxane(5 mL). To the reaction mixture was added 2N aqueous sodium carbonatesolution (2 mL). The cap was sealed and the reaction mixture was heatedat 85° C. for 2 hours. The reaction mixture was subsequently dilutedwith water (5 mL) and was extracted into EtOAc (2×30 mL). The combinedorganic phase was dried over sodium sulfate and evaporated to give theintermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-((E)-4-fluorostyryl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,which was treated with TFA (4 mL) for 1.5 hours to remove the protectinggroups. TFA was subsequently evaporated from the reaction mixture. Theresidual material was dissolved in DMSO (8 mL) and purified bypreparative HPLC, eluting with a gradient of 10-30% ACN (0.035% TFA) andwater (0.05% TFA). The pure product fractions were combined, evaporatedto a minimal volume, and lyophilized to give a TFA salt of the titlecompound as a tan solid (58 mg, 50%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.42-1.92 (m, 8H), 3.74 (br s, 1H), 4.40 (d, J=2.53 Hz, 2H), 4.51 (br s,1H), 6.86 (d, J=6.57 Hz, 1H), 7.27 (t, J=8.84 Hz, 1H), 7.56-7.73 (m,3H), 7.82 (br s, 3H), 8.14 (d, J=15.92 Hz, 1H), 8.49 (s, 1H). ESI-MS m/z[M+H]⁺calc'd for C₂₁H₂₂F₂N₄O, 385. found, 385.

Example 466-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(4-fluorostyryl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass vial, tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.299 mmol), (E)-4-fluorostyrylboronic acid (49.7 mg, 0.299mmol) and PdCl₂(PPh₃)₂ (42.0 mg, 0.060 mmol) were dissolved in dioxane(5 mL). To the reaction mixture was added 2N aqueous sodium carbonatesolution (2.0 mL). The cap was sealed and the reaction mixture washeated at 85° C. for 2 hours. The reaction mixture was subsequentlydiluted with water (5 mL) and extracted with EtOAc (2×30 mL). Thecombined organic phase was dried over sodium sulfate and evaporated togive the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-((E)-4-fluorostyryl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,which was treated with TFA (4 mL) at room temperature for 1 hour toremove the protecting groups. TFA was subsequently evaporated from thereaction mixture. The residual material was dissolved in DMSO (8 mL) andpurified by preparative HPLC, eluting with a gradient of 20-50% ACN(0.035% TFA) and water (0.05% TFA). The pure product fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a light yellow solid (32 mg, 28%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.77 (d, J=16.17 Hz, 1H), 2.00-2.21 (m, 1H),3.55-3.71 (m, 2H), 3.79-3.93 (m, 2H), 3.93-4.10 (m, 1H), 4.33-4.46 (m,2H), 4.54 (d, J=8.84 Hz, 1H), 7.15 (d, J=5.05 Hz, 1 H), 7.28 (t, J=8.84Hz, 1H), 7.58-7.74 (m, 3H), 7.93 (br s, 3H), 8.15 (d, J=15.92 Hz, 1H),8.51 (s, 1H). ESI-MS m/z [M+H]⁺calc'd for C₂₀H₂₀F₂N₄O₂, 387. found, 387.

Example 476-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-phenethyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass vial, tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.301 mmol), potassium trifluoro(phenethyl)borate (76 mg, 0.361mmol) and PdCl₂(PPh₃)₂ (42.2 mg, 0.060 mmol) were dissolved in dioxane(5 mL). To the reaction mixture was added 2N aqueous sodium carbonatesolution (2 mL). The cap was sealed and the reaction mixture was heatedat 85° C. for 2 hours. The reaction mixture was subsequently dilutedwith water (5 mL) and extracted with EtOAc (2×30 mL). The combinedorganic phase was dried over sodium sulfate and evaporated to give theintermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-phenethyl-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,which was treated with TFA (4 mL) at room temperature for 1 hour toremove the protecting groups. TFA was subsequently evaporated from thereaction mixture. The residual material was dissolved in DMSO (8 mL) andpurified by preparative HPLC, eluting with a gradient of 25-40% ACN(0.035% TFA) and water (0.05% TFA). The pure product fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a white solid (21 mg, 19%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.41 (br s, 2H), 1.65 (br s, 2H), 1.68-1.81 (m, 2H),1.84 (br s, 2H), 2.83-3.04 (m, 2H), 3.14-3.41 (m, 2H), 4.22-4.43 (m,3H), 6.65 (d, J=6.82 Hz, 1H), 7.08-7.33 (m, 4H), 7.37 (br s, 1H), 7.54(br s, 1H), 7.70 (br s, 3H), 8.31 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂₁H₂₅FN₄O, 369. found, 369.

Example 486-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-phenethyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass vial, tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.299 mmol), potassium trifluoro(phenethyl)borate (76 mg, 0.359mmol) and PdCl₂(PPh₃)₂ (42.0 mg, 0.060 mmol) were dissolved in dioxane(5 mL). To the reaction mixture was added 2N aqueous sodium carbonatesolution (2.0 mL). The cap was sealed and the reaction mixture washeated at 85° C. for 3 hours. The reaction mixture was subsequentlydiluted with water (5 mL) and extracted with EtOAc (2×30 mL). Thecombined organic phase was dried over sodium sulfate and evaporated togive the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-phenethyl-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,which was treated with TFA (4 mL) at room temperature for 1 hour toremove the protecting groups. TFA was subsequently evaporated from thereaction mixture. The residual material was dissolved in DMSO (8 mL) andpurified by preparative HPLC, eluting with a gradient of 20-55% ACN(0.035% TFA) and water (0.05% TFA). The pure product fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a light yellow solid (42 mg, 38%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.58-1.75 (m, 1H), 1.95-2.17 (m, 1H), 2.83-3.04(m, 2H), 3.16-3.32 (m, 1H), 3.32-3.46 (m, 1H), 3.47-3.61 (m, 1H), 3.66(d, J=11.37 Hz, 1H), 3.83-4.03 (m, 2H), 4.22-4.39 (m, 3H), 6.99 (d,J=5.05 Hz, 1H), 7.09-7.33 (m, 5H), 7.93 (br s, 2H), 8.32 (s, 1H). ESI-MSm/z [M+H]⁺calc'd for C₂₀H₂₃FN₄O₂, 371. found, 371.

Example 496-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(4-chlorophenethyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass vial, tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.299 mmol),2-(4-chlorophenethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (88 mg,0.329 mmol) and PdCl₂(PPh₃)₂ (63.1 mg, 0.090 mmol) were dissolved indioxane (5 mL). To the reaction mixture was added 2N aqueous sodiumcarbonate solution (2 mL). The cap was sealed and the reaction mixturewas heated at 85° C. for 2 hours. The reaction mixture was subsequentlydiluted with water (5 mL) and extracted with EtOAc (2×30 mL). Thecombined organic phase was dried over sodium sulfate and evaporated togive the intermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(4-chlorophenethyl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was dissolved in dichloromethane (3 mL) and treatedwith TFA (3 mL) at room temperature for 1 hour to remove the protectinggroups. The volatiles were subsequently evaporated from the reactionmixture and the residual material was dissolved in DMSO (8 mL) andpurified by preparative HPLC, eluting with a gradient of 20-65% ACN(0.035% TFA) and water (0.05% TFA). The pure product fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a white solid (43 mg, 36%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.68 (d, J=9.60 Hz, 1H), 1.90-2.15 (m, 1H),2.86-3.02 (m, 2H), 3.19-3.38 (m, 2H), 3.47-3.61 (m, 1H), 3.61-3.75 (m,2H), 3.81-4.03 (m, 2H), 4.13-4.41 (m, 3H), 6.99 (d, J=5.31 Hz, 1H), 7.22(m, J=8.34 Hz, 2H), 7.32 (m, J=8.34 Hz, 2H), 7.91 (br s, 3H), 8.33 (s,1H). ESI-MS m/z [M+H]⁺calc'd for C₂₀H₂₂ClFN₄O₂, 405. found, 405.

Example 506-((1R,2S)-2-Aminocyclohexylamino)-4-(4-chlorostyryl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass vial, tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.301 mmol), (E)-4-chlorostyrylboronic acid (54.8 mg, 0.301mmol) and PdCl₂(PPh₃)₂ (42.2 mg, 0.060 mmol) were dissolved in dioxane(5 mL). To the reaction mixture was added 2N aqueous sodium carbonatesolution (2.0 mL). The cap was sealed and the reaction mixture washeated at 85° C. for 3 hours. The reaction mixture was subsequentlydiluted with water (5 mL) and extracted with EtOAc (2×30 mL). Thecombined organic phase was dried over sodium sulfate and evaporated togive the intermediate, tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(4-chlorophenethyl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate,which was treated with TFA (4 mL) at room temperature for 1 hour toremove the protecting groups. TFA was subsequently evaporated from thereaction. The residual material was dissolved in DMSO (8 mL) andpurified by preparative HPLC, eluting with a gradient of 10-30% ACN(0.035% TFA) and water (0.05% TFA). The pure product fractions werecombined, evaporated to a minimal volume, and lyophilized to give a TFAsalt of the title compound as a pale yellow solid (31 mg, 26%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.48 (d, J=6.82 Hz, 2H), 1.62 (d, J=7.58 Hz,1H), 1.66-1.80 (m, 3H), 1.80-2.02 (m, 2H), 3.74 (br s, 1H), 4.41 (d,J=2.27 Hz, 1H), 4.50 (br s, 1H), 6.86 (d, J=5.56 Hz, 1H), 7.50 (d,J=8.59 Hz, 1H), 7.56-7.68 (m, 2H), 7.69 (s, 1H), 7.76 (br s, 3H), 8.21(d, J=15.92 Hz, 1H), 8.51 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂₁H₂₂ClFN₄O, 401. found, 401.

Example 516-(3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(4-chlorostyryl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

In a 30 mL sealed cap glass vial, tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(150 mg, 0.299 mmol), (E)-4-chlorostyrylboronic acid (54.6 mg, 0.299mmol) and PdCl₂(PPh₃)₂ (42.0 mg, 0.060 mmol) were dissolved in dioxane(5 mL). To the reaction mixture was added 2N aqueous sodium carbonatesolution (2 mL). The cap was sealed and the reaction mixture was heatedat 85° C. for 2 hours. The reaction mixture was subsequently dilutedwith water (5 mL) and extracted with EtOAc (2×30 mL). The combinedorganic phase was dried over sodium sulfate and evaporated to give theintermediate, tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-((E)-4-chlorostyryl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate.The intermediate was diluted with dichloromethane (3.0 mL) and treatedwith TFA (3 mL) for 1.5 hours to remove the protecting groups. Thevolatiles were subsequently evaporated from the reaction mixture, andthe residual material was dissolved in DMSO (8 mL) and purified bypreparative HPLC, eluting with 20-60% ACN (0.035% TFA) and water (0.05%TFA). The pure product fractions were combined, evaporated to a minimalvolume, and lyophilized to give a TFA salt of the title compound as apale yellow solid (42 mg, 35%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.77 (d,J=15.66 Hz, 1H), 1.98-2.22 (m, 1H), 3.50-3.73 (m, 2H), 3.79-4.08 (m,3H), 4.32-4.51 (m, 2H), 4.55 (br s, 1H), 7.17 (d, J=5.05 Hz, 1H), 7.50(d, J=8.59 Hz, 2H), 7.55-7.73 (m, 2H), 7.92 (d, J=4.55 Hz, 3H), 8.22 (d,J=16.17 Hz, 1H), 8.53 (s, 1H). ESI-MS m/z [M+H]⁺calc'd forC₂₀H₂₀ClFN₄O₂, 403. found, 403.

Example 52(R)-6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(5-fluoropyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

and

Example 53(S)-6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(5-fluoropyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A mixture tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-chloro-7-fluoro-1-methyl-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(200 mg, 0.390 mmol),5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(153 mg, 0.585 mmol), potassium carbonate (108 mg, 0.780 mmol), Pd-118(10 mg, 0.016 mmol) in DMA (10 mL) and water (0.67 mL) was stirred at80° C. for 20 h. The solution was worked up and treated with TFA (3 mL)and DCM (6 mL) at room temperature for 1 h and was subsequently purifiedvia preparative HPLC to give TFA salts of the title compounds as tan (40mg, 25%) and white solids (35 mg, 22%), respectively.

EXAMPLE 52: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35-1.56 (m, 5H), 1.67-1.80(m, 2H), 1.84-2.00 (m, 1H), 3.74 (br s, 1H), 4.48 (br s, 1H), 4.77 (q,J=6.65 Hz, 1H), 6.87 (d, J=6.28 Hz, 1H), 7.08 (td, J=7.31, 2.65 Hz, 1H),7.82 (br s, 2H), 8.06 (dd, J=9.92, 2.59 Hz, 1H), 8.51 (s, 1H), 8.88 (dd,J=7.44, 5.37 Hz, 1H), 9.46 (s, 1H). [M+H] calc'd for C₂₁H₂₂F₂N₆O, 413.found, 413.

EXAMPLE 53: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36-1.60 (m, 4H), 1.60-1.83(m, 3H), 1.90-2.06 (m, 1H), 3.73 (br s, 1H), 4.46 (br s, 1H), 4.76 (q,J=6.39 Hz, 1H), 6.93 (d, J=6.35 Hz, 1H), 7.02-7.15 (m, 1H), 7.90-8.14(m, 3H), 8.51 (s, 1H), 8.88 (dd, J=7.29, 5.46 Hz, 1H), 9.47 (s, 1H).[M+H] calc'd for C₂₁H₂₂F₂N₆O, 413. found, 413.

Example 54(R)-6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-1-methyl-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

and

Example 55(S)-6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-1-methyl-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A mixture of tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclo-hexyl)amino)-4-chloro-7-fluoro-1-methyl-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(100 mg, 0.195 mmol),5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(75 mg, 0.292 mmol), potassium carbonate (54 mg, 0.390 mmol), Pd-118 (5mg, 0.008 mmol) in DMA (6 mL) and water (0.33 mL) was stirred at 80° C.for 20 h. The solution was worked up and treated with TFA (3 mL) and DCM(6 mL) at room temperature for 1 h. The mixture was purified viapreparative HPLC to give TFA salts of the title compounds as whitesolids (24 mg, 30% and 18 mg, 23%, respectively).

EXAMPLE 54: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.34-1.53 (m, 5H), 1.61 (d,J=12.39 Hz, 1H), 1.66-1.84 (m, 3H), 1.88 (d, J=9.58 Hz, 1H), 1.96 (dd,J=13.64, 4.55 Hz, 1H), 2.46 (s, 3H), 3.76 (br s, 1H), 4.16-4.29 (m, 1H),4.81 (q, J=6.39 Hz, 1H), 7.17 (d, J=5.74 Hz, 1H), 7.81 (br s, 2H),8.71-8.80 (m, 2H). [M+H] calc'd for C₂₂H₂₅FN₆O, 409. found, 409.

EXAMPLE 55: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17-1.32 (m, 3H), 1.32-1.54(m, 4H), 1.61-1.82 (m, 3H), 1.84-2.01 (m, 1H), 2.37-2.46 (m, 2H),3.67-3.82 (m, 1H), 4.52 (br s, 1H), 4.75 (q, J=6.61 Hz, 1H), 6.80 (d,J=6.65 Hz, 1H), 6.88 (dd, J=7.02, 1.77 Hz, 1H), 7.68-7.85 (m, 2H), 8.18(s, 1H), 8.46 (s, 1H), 8.65 (d, J=7.02 Hz, 1H), 9.30 (s, 1H). [M+H]calc'd for C₂₂H₂₅FN₆O, 409. found, 409.

Example 56(R)-6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-1-methyl-4-(3-methylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

and

Example 57(S)-6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-1-methyl-4-(3-methylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

A mixture of tert-butyl((3R,4R)-4-((4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)amino)tetrahydro-2H-pyran-3-yl)carbamate(75 mg, 0.133 mmol), 3-methyl-5-(tributylstannyl)isothiazole (77 mg,0.199 mmol), tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027mmol) in toluene (5 mL) was heated at 140° C. in a microwave for 8 h.The reaction mixture was diluted with EtOAc (200 mL) and washed withbrine (200 mL). The organics were dried and concentrated. The resultingmaterial was dissolved in TFA (5 mL) and stirred at 60° C. for 3 h. Themixture was purified via preparative HPLC to give TFA salts of the titlecompounds (12 mg, 24% and 9 mg, 18%, respectively).

EXAMPLE 56: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.88 (t, J=5.62 Hz, 2H),1.43 (d, J=10.0 Hz, 3H), 2.36 (m, 1H), 2.52 (m, 3H), 2.64 (m, 1H), 3.29(m, 1H), 3.62 (m, 1H), 3.78 (d, J=10 Hz, 1H), 4.00 (m, 1H), 4.43 (d,J=10.0 Hz, 1H), 6.52 (s, 1H), 5.62 (d, J=5.62 Hz, 1H), 8.75 (s, 1H),8.78 (s, 1H). [M+H] calc'd for C₁₇H₂₀FN₅O₂S, 378. found, 378.

EXAMPLE 57: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.88 (t, J=10.0 Hz, 2H),1.43 (d, J=10.0 Hz, 3H), 2.07 (m, 1H), 2.36 (m, 1H), 2.49 (m, 3H), 2.63(m, 1H), 3.62 (m, 1H), 3.78 (m, 1H), 4.00 (m, 1H), 4.82 (d, J=10.0 Hz,1H), 6.52 (s, 1H), 7.43 (d, J=5.0 Hz, 1H), 8.75 (s, 1H), 8.79 (s, 1H).[M+H] calc'd for C₁₇H₂₀FN₅O₂S, 378. found, 378.

Example 586-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

STEP A: tert-Butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a 25 mL reaction flask equipped with magnetic stir bar andthermometer was added tert-butyl6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(200 mg, 0.399 mmol) and5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(124 mg, 0.479 mmol), followed by potassium carbonate (325 mesh powder)(110 mg, 0.798 mmol), DMA (10 mL), and water (0.667 mL). The mixture wasstirred at room temperature for 3 min before degassing with vacuum andN₂ back-fill (5×). To the resulting deep purple mixture was added Pd-118(10.89 mg, 0.016 mmol). The reaction mixture was degassed again withvacuum and N₂ back-fill (5×). The flask was wrapped tightly with plasticfilm, placed in an oil bath, and the reaction mixture was stirred at 80°C. for 18 hours. Solid N-acetyl cysteine (65.2 mg, 0.399 mmol) was addedand the mixture was stirred at 70° C. for 2 h. The mixture wassubsequently diluted with water and extracted with EtOAc (200 mL). Theorganic layer was dried and concentrated to give a residue, which waspurified by preparative HPLC, eluting with a gradient of 45-70% ACN(0.035% TFA) and water (0.05% TFA). The fractions were collected togive, upon basic work-up, the title compound as a light yellow solid (50mg, 21%).

STEP B:6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a solution of tert-butyl6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(45 mg, 0.075 mmol) in isopropanol (5 mL) at 65° C. was addedconcentrated HCl (0.268 mL, 3.21 mmol) dropwise. The reaction mixturewas stirred at 65° C. overnight and then slowly cooled. The solids werefiltered and dried to give an HCl salt of the title compound as a paleyellow solid (30 mg, 92%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.84 (d,J=9.88 Hz, 1H), 2.08-2.22 (m, 1H), 2.46 (s, 3H), 3.55-3.67 (m, 2H),3.94-4.09 (m, 2H), 4.35-4.47 (m, 2H), 6.88 (dd, J=7.08, 1.83 Hz, 1H),7.12 (d, J=5.98 Hz, 1H), 8.03 (d, J=3.97 Hz, 2H), 8.15 (s, 1H), 8.39 (s,1H), 8.66 (d, J=7.08 Hz, 1H), 9.24 (s, 1H). [M+H] calc'd forC₂₀H₂₁FN₆O₂, 397. found, 397.

Example 596-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

STEP A: tert-Butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a 25 mL reaction flask equipped with magnetic stir bar andthermometer was added tert-butyl6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(200 mg, 0.401 mmol) and5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(124 mg, 0.481 mmol), followed by potassium carbonate (325 mesh powder)(111 mg, 0.802 mmol), DMA (6 mL), and water (0.400 mL). The mixture wasstirred at room temperature for 3 min before degassing with vacuum andN₂ back-fill (5×). To the resulting deep purple mixture was added Pd-118(10.93 mg, 0.016 mmol). The reaction mixture was degassed again withvacuum and N₂ back-fill (5×). The flask was wrapped tightly with plasticfilm, placed in an oil bath, and the reaction mixture was stirred at 80°C. for 18 hours. Solid N-acetyl cysteine (65.4 mg, 0.401 mmol) was addedand the mixture was stirred at 70° C. for 2 h. The mixture wassubsequently diluted with water and extracted with EtOAc (200 mL). Theorganic layer was dried and concentrated to give a residue, which waspurified by preparative HPLC, eluting with a gradient of 55-80% ACN(0.035% TFA) and water (0.05% TFA). The fractions were collected togive, upon basic work-up, the title compound as a light yellow solid(110 mg, 46%).

STEP B:6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

To a solution of tert-butyl6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclo-hexyl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(110 mg, 0.185 mmol) in isopropanol (10 mL) at 65° C. was addedconcentrated HCl (0.268 mL, 3.21 mmol) dropwise. The reaction mixturewas stirred at 65° C. overnight and then slowly cooled. The solids werefiltered and dried to give an HCl salt of the title compound as a paleyellow solid (75 mg, 94%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.49 (br s,1H) 1.61-1.82 (m, 1H) 1.96 (d, J=8.79 Hz, 1H) 2.44 (s, 3H), 4.33-4.45(m, 2H) 6.81 (d, J=6.35 Hz, 1H) 6.88 (dd, J=7.02, 1.83 Hz, 1H) 7.90 (brs, 2H) 8.20 (s, 1H) 8.37 (s, 1H) 8.66 (d, J=7.02 Hz, 1H) 9.33 (s, 1H).[M+H] calc'd for C₂₁H₂₃FN₆O, 395. found, 395.

Table 1, below, lists compounds that can be made in a manner similar toExample 39 (Examples 60-67), Example 24 (Examples 68-76), Example 41(Example 77), Example 29 (Examples 78-84), and Example 35 (Examples85-91).

TABLE 1 EXAMPLES 60-91 Example Structure 60

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(indolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 61

  2-(6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine- 7-carbonitrile 62

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(7-fluoroindolizin- 2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 63

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin- 3(2H)-one 64

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-b]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 65

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(3-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c] pyridin-3(2H)-one 66

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-a]imidazol-6-yl)-1H-pyrrolo[3,4-c] pyridin-3(2H)-one 67

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(pyrrolo[2,1-b]oxazol-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 68

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(indolizin-2-yl)-1H-pyrrolo [3,4-c]pyridin-3(2H)-one 69

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl) indolizine-7-carbonitrile70

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(7-fluoroindolizin-2-yl)-1H-pyrrolo [3,4-c]pyridin-3(2H)-one 71

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 72

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-b]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 73

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 74

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-a] imidazol-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 75

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(pyrrolo[2,1-b]oxazol-6-yl)- 1H-pyrrolo[3,4-c]pyridin-3(2H)-one76

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(8-oxo-5,6,7,8-tetrahydroindolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 77

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(8-oxo-5,6,7,8-tetrahydro-indolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin- 3(2H)-one 78

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(3-methyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo [3,4-c]pyridin-3(2H)-one79

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(3,3-dimethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo [3,4-c]pyridin-3(2H)-one 80

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(3-ethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 81

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(3-isopropyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 82

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin- 3(2H)-one 83

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(2-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 84

  6-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(2-ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 85

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(3-methyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 86

  6-(((1R,2S)-2-aminocyclohexyl)amino)-4-(3,3-dimethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 87

  6-(((1R,2S)-2-aminocyclohexyl)amino)-4-(3-ethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 88

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(3-isopropyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 89

  6-(((1R,2S)-aminocyclohexyl)amino)-7-fluoro-4-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 90

  6-(((1R,2S)-2-aminocyclohexyl)amino)-7-fluoro-4-(2-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one 91

  6-(((1R,2S)-2-aminocyclohexyl)amino)-4-(2-ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one

Table 2, below, lists SYK inhibition data for many of the compoundsdescribed in the examples, where larger pIC₅₀ values represent higherpotency. The compounds were tested in accordance with the assaydescribed on page 47 of the specification.

TABLE 2 SYK Inhibition (pIC₅₀) for Example Compounds Example # pIC₅₀ 17.3 2 8.4 3 8.9 4 7.9 5 8.4 6 9.1 7 9.7 8 7.7 9 9.7 10 9.2 11 8.0 12 7.913 9.6 14 9.8 15 9.8 16 9.5 17 9.6 18 9.5 19 9.8 20 9.6 21 9.5 22 9.9 239.4 24 9.4 25 7.9 26 8.3 27 8.3 28 8.8 29 10.0 30 10.0 31 9.9 32 9.7 339.2 34 8.9 35 8.0 36 9.9 37 9.5 38 7.7 39 8.7 40 9.7 41 7.7 42 9.2 437.2 44 7.2 45 8.6 46 8.3 47 7.0 48 7.0 49 7.2 50 8.7 51 8.7 52 7.4 536.4 54 7.3 55 6.6 56 7.8 57 7.0 58 7.9 59 8.6

As used in this specification and the appended claims, singular articlessuch as “a,” “an,” and “the,” may refer to a single object or to aplurality of objects unless the context clearly indicates otherwise.Thus, for example, reference to a composition containing “a compound”may include a single compound or two or more compounds. It is to beunderstood that the above description is intended to be illustrative andnot restrictive. Many embodiments will be apparent to those of skill inthe art upon reading the above description. Therefore, the scope of theinvention should be determined with reference to the appended claims andincludes the full scope of equivalents to which such claims areentitled. The disclosures of all articles and references, includingpatents, patent applications and publications, are herein incorporatedby reference in their entirety and for all purposes.

1. A compound of Formula 1,

or a pharmaceutically acceptable salt thereof, wherein: G is selectedfrom 0 and CH₂; R¹ and R² are each independently selected from hydrogen,halo, C₁₋₃ alkyl, and C₁₋₃ haloalkyl; or R¹ and R², together with theatom to which they are attached, form a C₃₋₆ cycloalkylidene; eachR^(3a) is independently selected from halo, oxo, —NO₂, —CN, R⁶, and R⁷;R⁴ is selected from

wherein

represents a point of attachment; R^(4a) and R^(4b) are eachindependently selected from hydrogen, halo, —CN, R⁶, and R⁷, providedthat (a) if R^(4a) is hydrogen, then R^(4b) is not unsubstituted methyl;(b) if R^(4b) is hydrogen, then R^(4a) is not hydrogen or unsubstitutedmethyl; and (c) if R^(4b) is hydrogen and G is O, then R^(4a) is notchloro; or R^(4a) and R^(4b), together with the atoms to which they areattached, form a phenylene or a C₃₋₅ heteroarylene, each optionallysubstituted with from one to four substituents independently selectedfrom halo, oxo, —CN, R⁶, and R⁷, wherein the C₃₋₅ heteroarylene moietyhas 5 or 6 ring atoms and 1 or 2 are heteroatoms, each of theheteroatoms being N; R^(4c) is selected from hydrogen, halo, —CN, R⁶,and R⁷, provided that when G is O, R^(4c) is not unsubstituted methyl;R^(4d) and R^(4e) are each independently selected from hydrogen, halo,—CN, R⁶, and R⁷; or R^(4d) and R^(4e), together with the atoms to whichthey are attached, form a C₃₋₅ heterocycle-diyl or a C₃₋₅ heteroarylene,each having 5 or 6 ring atoms, at least one heteroatom which is N, andoptionally 1 or 2 additional heteroatoms independently selected from N,O, and S, and wherein the C₃₋₅ heterocycle-diyl or the C₃₋₅heteroarylene is optionally substituted with from one to foursubstituents independently selected from halo, oxo, —CN, R⁶, and R⁷;R^(4f) is selected from C₃₋₈ cycloalkyl, C₂₋₅ heterocyclyl, C₆₋₁₄ aryl,and C₁₋₉ heteroaryl, each optionally substituted with from one to fivesubstituents independently selected from halo, oxo, —CN, R⁶, and R⁷;R^(4g) and R^(4h) are each independently selected from hydrogen, halo,C₁₋₃ alkyl, and C₁₋₃ haloalkyl; or R^(4g) and R^(4h), together with theatom to which they are attached, form a C₃₋₆ cycloalkylidene; R⁵ isselected from hydrogen, halo, —CN, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₂₋₅ heterocyclyl, C₁₋₅ heteroaryl, and R¹⁰, wherein the alkyl,alkenyl, and alkynyl moieties are each optionally substituted with fromone to five substituents independently selected from halo, —CN, oxo, andR¹⁰, and wherein the heterocyclyl moiety has 3 to 6 ring atoms and theheteroaryl moiety has 5 or 6 ring atoms, and the heterocyclyl andheteroaryl moieties are each optionally substituted with from one tofour substituents independently selected from halo, —NO₂, —CN, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and R¹⁰; each R⁶ isindependently selected from —OR⁸, —N(R⁸)R⁹, —NR⁸C(O)R⁹, —C(O)R⁸,—C(O)OR⁸, —C(O)N(R⁸)R⁹, —C(O)N(R⁸)OR⁹, —C(O)N(R⁸)S(O)₂R⁹, —N(R⁸)S(O)₂R⁹,—S(O)_(n)R⁸, and —S(O)₂N(R⁸)R⁹; each R⁷ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl-(CH₂)_(m)—,C₆₋₁₄ aryl-(CH₂)_(m)—, C₂₋₅ heterocyclyl-(CH₂)_(m)—, and C₁₋₉heteroaryl-(CH₂)_(m)—, each optionally substituted with from one to fivesubstituents independently selected from halo, oxo, —NO₂, —CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, and R¹⁰; each R⁸ and R⁹ is independently selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl-(CH₂)_(m)—, C₆₋₁₄ aryl-(CH₂)_(m)—, C₂₋₅heterocyclyl-(CH₂)_(m)—, and C₁₋₉ heteroaryl-(CH₂)_(m)—, eachnon-hydrogen substituent optionally substituted with from one to fivesubstituents independently selected from halo, oxo, —NO₂, —CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, and R¹⁰; each R¹⁰ is independently selected from—OR¹¹, —N(R¹¹)R¹², —N(R¹¹)C(O)R¹², —C(O)R¹¹, —C(O)OR¹¹, —C(O)N(R¹¹)R¹²,C(O) N(R¹¹)OR¹², —C(O)N(R¹¹)S(O)₂R¹², —NR¹¹—S(O)_(n)R¹¹, and—S(O)₂N(R¹¹)R¹²; each R¹¹ and R¹² is independently selected fromhydrogen and C₁₋₆ alkyl; each n is independently selected from 0, 1 and2; each m is independently selected from 0, 1, 2, 3, and 4; each p isindependently selected from 0, 1, 2, 3, 4, 5, and 6; wherein each of theheteroaryl moieties recited for R^(4f), R⁷, R⁸, and R⁹ has 1 to 4heteroatoms independently selected from N, O, and S, and each of theheterocyclyl moieties recited for R^(4f), R⁷, R⁸, and R⁹ has 1 or 2heteroatoms independently selected from N, O, and S.
 2. A compound orpharmaceutically acceptable salt according to claim 1, wherein R¹ and R²are both hydrogen.
 3. A compound or pharmaceutically acceptable saltaccording to claim 1, wherein R⁵ is selected from hydrogen, halo, andC₁₋₄ alkyl.
 4. A compound or pharmaceutically acceptable salt accordingto claim 1, wherein p is
 0. 5. A compound or pharmaceutically acceptablesalt according to claim 1, wherein R⁴ is selected from:


6. A compound or pharmaceutically acceptable salt according to claim 5,wherein R⁴ is


7. A compound or pharmaceutically acceptable salt according to claim 5,wherein R⁴ is


8. A compound or pharmaceutically acceptable salt according to claim 5,wherein R⁴ is


9. A compound or pharmaceutically acceptable salt according to claim 1,wherein R⁴ is selected from:


10. A compound or pharmaceutically acceptable salt according to claim 1,wherein G is CH₂.
 11. A compound or pharmaceutically acceptable saltaccording to claim 1, wherein G is O.
 12. A compound according to claim1, which is selected from the following compounds:6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-(difluoromethyl)isothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(isothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(isothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(3-cyclopropylisothiazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;5-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiophene-2-carbonitrile;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;5-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiophene-2-carbonitrile;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(5-fluorothiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[2,3-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[2,3-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[3,2-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[3,2-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(6-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(6-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;2-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzo[b]thiophene-5-carbonitrile;2-(6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzo[b]thiophene-5-carbonitrile;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(4-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(4-fluorobenzo[b]thiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(thieno[3,2-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(thieno[3,2-b]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(4-fluorothiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(4-fluorothiophen-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;Ethyl2-(6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carboxylate;2-(6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carboxylicacid;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(1-oxo-2,3-dihydro-1H-pyrrolizin-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(3-methylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(4-fluorostyryl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(4-fluorostyryl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-phenethyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-phenethyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(4-chlorophenethyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((1R,2S)-2-Aminocyclohexylamino)-4-(4-chlorostyryl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-ylamino)-4-(4-chlorostyryl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;(R)-6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(5-fluoropyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;(S)-6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(5-fluoropyrazolo[1,5-a]pyridin-3-yl)-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;(R)-6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-1-methyl-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;(S)-6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-1-methyl-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;(R)-6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-1-methyl-4-(3-methylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;(S)-6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-1-methyl-4-(3-methylisothiazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;a stereoisomer of any of the aforementioned compounds; and apharmaceutically acceptable salt of any of the aforementioned compoundsor stereoisomers.
 13. A compound according to claim 1, which is selectedfrom the following compounds:6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(indolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;2-(6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carbonitrile;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(7-fluoroindolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-b]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-a]imidazol-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(pyrrolo[2,1-b]oxazol-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(indolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;2-(6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)indolizine-7-carbonitrile;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(7-fluoroindolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-b]pyrazol-5-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(1-methyl-1H-pyrrolo[1,2-a]imidazol-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(pyrrolo[2,1-b]oxazol-6-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(8-oxo-5,6,7,8-tetrahydroindolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(8-oxo-5,6,7,8-tetrahydroindolizin-2-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(3-methyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-4-(3,3-dimethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-4-(3-ethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(3-isopropyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(2-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)amino)-4-(2-ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(3-methyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-4-(3,3-dimethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-4-(3-ethyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(3-isopropyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-7-fluoro-4-(2-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;6-(((1R,2S)-2-Aminocyclohexyl)amino)-4-(2-ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one;a stereoisomer of any of the aforementioned compounds; and apharmaceutically acceptable salt of any of the aforementioned compoundsor stereoisomers.
 14. A compound which is6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one, a stereoisomer thereof, or a pharmaceutically acceptable saltof the compound or stereoisomer.
 15. A pharmaceutical compositioncomprising: a compound or pharmaceutically acceptable salt as defined inclaim 1; and a pharmaceutically acceptable excipient. 16-17. (canceled)18. A method of treating a disease or condition in a subject for which aSYK inhibitor is indicated, the method comprising administering to thesubject an effective amount of a compound or pharmaceutically acceptablesalt as defined in claim
 1. 19. A method of treating a disease orcondition in a subject, the method comprising administering to thesubject an effective amount of a compound or pharmaceutically acceptablesalt as defined in claim 1, wherein the disease or condition is selectedfrom allergic rhinitis, allergic asthma, atopic dermatitis, rheumatoidarthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis,immune thrombocytopenic purpura, inflammatory bowel disease, Behcet'sdisease, graft versus host disease, chronic obstructive pulmonarydisease, and thrombosis.
 20. A method of treating a disease or conditionin a subject, the method comprising administering to the subject aneffective amount of a compound or pharmaceutically acceptable salt asdefined in claim 1, wherein the disease or condition is selected fromcancer.
 21. A method according to claim 20, wherein the disease orcondition is selected from acute myeloid leukemia, B-cell chroniclymphocytic leukemia, B-cell lymphoma, and T-cell lymphoma.
 22. A methodaccording to claim 20, wherein the disease or condition is selected frombrain cancer, lung cancer, squamous cell cancer, bladder cancer, gastriccancer, pancreatic cancer, breast cancer, cancer of the head, neckcancer, renal cancer, kidney cancer, ovarian cancer, prostate cancer,colorectal cancer, prostate cancer, colon cancer, epidermoid cancer,esophageal cancer, testicular cancer, gynecological cancer, and thyroidcancer.
 23. A combination of an effective amount of a compound orpharmaceutically acceptable salt as defined in claim 1, and at least oneadditional pharmacologically active agent.
 24. A combination accordingto claim 23, wherein the additional pharmacologically active agent is aDMARD.
 25. A combination according to claim 24, wherein the DMARD ismethotrexate.